EP1213288B1 - Propanoic acid derivatives that inhibit the binding of integrins to their receptors - Google Patents

Propanoic acid derivatives that inhibit the binding of integrins to their receptors Download PDF

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Publication number
EP1213288B1
EP1213288B1 EP01125495A EP01125495A EP1213288B1 EP 1213288 B1 EP1213288 B1 EP 1213288B1 EP 01125495 A EP01125495 A EP 01125495A EP 01125495 A EP01125495 A EP 01125495A EP 1213288 B1 EP1213288 B1 EP 1213288B1
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EP
European Patent Office
Prior art keywords
amino
methyl
propanoic acid
hexanoyl
oxopyridin
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EP01125495A
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German (de)
French (fr)
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EP1213288A1 (en
Inventor
Ronald J. Biediger
George W. Holland
Jamal M. Kassir
Wen Li
Robert V. Market
Ian L. Scott
Brian Dupre
Linda K. Hamaker
Noel Nguyen
Radford E. Decker
Chengde Wu
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Encysive Pharmaceuticals Inc
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Encysive Pharmaceuticals Inc
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/62—Oxygen or sulfur atoms
    • C07D213/63—One oxygen atom
    • C07D213/64—One oxygen atom attached in position 2 or 6
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D317/00—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms
    • C07D317/08—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3
    • C07D317/44—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 ortho- or peri-condensed with carbocyclic rings or ring systems
    • C07D317/46—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 ortho- or peri-condensed with carbocyclic rings or ring systems condensed with one six-membered ring
    • C07D317/48—Methylenedioxybenzenes or hydrogenated methylenedioxybenzenes, unsubstituted on the hetero ring
    • C07D317/50—Methylenedioxybenzenes or hydrogenated methylenedioxybenzenes, unsubstituted on the hetero ring with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to atoms of the carbocyclic ring
    • C07D317/60—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing three or more hetero rings

Definitions

  • This invention is directed generally to the inhibition of the binding of ⁇ 4 ⁇ 1 integrin to its receptors, for example VCAM-1 (vascular cell adhesion molecule-1) and fibronectin.
  • VCAM-1 vascular cell adhesion molecule-1
  • fibronectin vascular cell adhesion molecule-1
  • the invention also relates to compounds that inhibit this binding, to pharmaceutically active compositions comprising such compounds and to the use of such compounds either as above, or in formulations for the control or prevention of disease states in which ⁇ 4 ⁇ 1 is involved.
  • white blood cells also called leukocytes
  • a tissue has been invaded by a microorganism or has been damaged
  • white blood cells also called leukocytes
  • a cell adhesion event One of the most important aspects of the inflammatory response involves the cell adhesion event.
  • white blood cells are found circulating through the bloodstream.
  • the white blood cells recognize the invaded or damage tissue, bind to the wall of the capillary and migrate through the capillary into the affected tissue. These events are mediated by a family of proteins called cell adhesion molecules.
  • the integrin ⁇ 4 ⁇ 1 (also called VLA-4 for very late-antigen-4) is a heterodimeric protein expressed on the surface of monocytes, lymphocytes and two subclasses of granulocytes: eosinophils and basophils. This protein plays a key role in cell adhesion through its ability to recognize and bind VCAM-1 and fibronectin, proteins associated with the endothelial cells that line the interior wall of capillaries.
  • endothelial cells express a series of adhesion molecules, including VCAM-1, that are critical for binding the white blood cells that are necessary for fighting infection.
  • VCAM-1 adhesion molecules
  • the white blood cells Prior to binding to VCAM-1 or fibronectin, the white blood cells initially bind to certain adhesion molecules to slow their flow and allow the cells to "roll" along the activated endothelium. Monocytes, lymphocytes, basophils and eosinophils are then able to firmly bind to VCAM-1 or fibronectin on the blood vessel wall via the ⁇ 4 ⁇ 1 integrin. There is evidence that such interactions are also involved in transmigration of these white blood cells into the damaged tissue, as well as the initial rolling event itself.
  • ⁇ 4 ⁇ 1 Some of the diseases that might be treated by the inhibition of ⁇ 4 ⁇ 1 binding include, but are not limited to, atherosclerosis, rheumatoid arthritis, asthma, allergy, multiple sclerosis, lupus, inflammatory bowel disease, graft rejection, contact hypersensitivity, and type I diabetes.
  • ⁇ 4 ⁇ 1 is also found on various cancer cells, including leukemia, melanoma, lymphoma and sarcoma cells. It has been suggested that cell adhesion involving ⁇ 4 ⁇ 1 may be involved in the metastasis of certain cancers. Inhibitors of ⁇ 4 ⁇ 1 binding may, therefore, also be useful in the treatment of some forms of cancer.
  • WO 99/52943 describes a method for expressing T cell receptors and suitable vectors. Also disclosed are cells that are transfected with these vectors and express the desired T cell receptors.
  • EP 512831 discloses substituted amides as fibrinogen receptor antagonists useful for inhibition of binding of fibrinogen to blood platelets and inhibition of their aggregation.
  • WO 9804247 discloses amide derivatives as inhibitors of integrins, in particular, integrins of ⁇ 4 ⁇ 1 and ⁇ IIb ⁇ IIIa subfamilies.
  • the invention is directed to novel compounds selected from the group consisting of (3S)-3- ⁇ [(2S)-2-(3-benzyl-5-methyl-2-oxopyridin-1 (2H)-yl)hexanoyl]amino ⁇ -3-(3',4'-dimethoxy-1,1'-biphenyl-4-yl)propanoic acid, (3S)-3-( ⁇ (2S)-2-[3-(2-chlorobenzyl)-5-methyl-2-oxopyridin-1 (2H)-yl]hexanoyl ⁇ amino)-3-(3',4'-dimethoxy-1,1'-biphenyl-4-yl)propanoic acid, (3S)-3-(1,1'-biphenyl-4-yl)-3-( ⁇ (2S)-2-[3-(2-chloro-6-methylbenzyl)-5-methyl-2-oxopyridin-1(2H)-yl]hexan
  • a presently most preferred compound is (3S)-3-(1,3-benzodioxol-5-yl)-3-((2S)-2-(3-benzyl-5-methyl-2-oxo-1(2H)-pyridinyl)hexanoyl)amino)propanoic acid or a pharmaceutically acceptable salt thereof.
  • the present invention also relates to pharmaceutical compositions comprising a physiologically acceptable diluent and at least one compound of the present invention.
  • the present invention further relates to the use of a compound of the invention for manufacturing a medicament for treating a disease selected from the group consisting of asthma, atherosclerosis, rheumatoid arthritis, allergy, multiple sclerosis, lupus, inflammatory bowel disease, graft rejection, contact hypersensitivity, type I diabetes, leukaemia, and brain cancer.
  • a disease selected from the group consisting of asthma, atherosclerosis, rheumatoid arthritis, allergy, multiple sclerosis, lupus, inflammatory bowel disease, graft rejection, contact hypersensitivity, type I diabetes, leukaemia, and brain cancer.
  • the invention further relates to a compound of the invention for use as a medicament.
  • BOC for t-butyloxycarbonyl
  • EtOAc for ethyl acetate
  • DMF for dimethylformamide
  • THF for tetrahydrofuran
  • Tos for p-toluenesulfonyl
  • DCC for dicyclohexylcarbodiimide
  • HOBT for 1-hydroxybenzotriazole
  • TFAA for trifluoroacetic anhydride
  • NMM for N-methyl morpholine
  • DIPEA for diisopropylethylamine
  • DCM for methylene dichloride
  • LHMDS for lithium hexamethyl disilazide
  • NaHMDS for sodium hexamethyl disilazide
  • CDI for 1,1'-carbonyldiimidazole HBTU for O-benzotriazol-1-yl-N,N,N', N'-tetramethyluronium hexafluorophosphate, EDCI
  • Amino acids are abbreviated as follows: C for L-cysteine; D for L-aspartic acid; E for L-glutamic acid; G for glycine; H for L-histidine; I for L-isoleucine; L for L-leucine; N for L-asparagine; P for L-proline; Q for L-glutamine; S for L-serine; T for L-threonine; V for L-valine, and W for L-tryptophan.
  • the compounds of the present invention can be used in the form of pharmaceutically acceptable salts derived from inorganic or organic acids.
  • pharmaceutically acceptable salt means those salts which are, within the scope of sound medical judgement, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response and the like and are commensurate with a reasonable benefit/risk ratio.
  • Pharmaceutically acceptable salts are well-known in the art. For example, S. M. Berge et al. describe pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences, 1977, 66: 1 et seq.
  • the salts can be prepared in situ during the final isolation and purification of the compounds of the invention or separately by reacting a free base function with a suitable organic acid.
  • Representative acid addition salts include, but are not limited to acetate, adipate, alginate, citrate, aspartate, benzoate, benzene sulfonate, bisulfate, butyrate, camphorate, camphor sulfonate, digluconate, glycerophosphate, hemisulfate, heptanoate, hexanoate, fumarate, hydrochloride, hydrobromide, hydroiodide, 2-hydroxyethansulfonate (isothionate), lactate, maleate, methane sulfonate, nicotinate, 2-naphthalene sulfonate, oxalate, palmitoate, pectinate, persulfate, 3-phenylpropionate, picrate, pivalate, propionate, succinate, tartrate, thiocyanate, phosphate, glutamate, bicarbonate, p-toluene sulfonate and
  • the basic nitrogen-containing groups can be quatemized with such agents as lower alkyl halides such as methyl, ethyl, propyl, and butyl chlorides, bromides and iodides; dialkyl sulfates like dimethyl, diethyl, dibutyl and diamyl sulfates; long chain halides such as decyl, lauryl, myristyl and stearyl chlorides, bromides and iodides; arylalkyl halides like benzyl and phenethyl bromides and others. Water or oil-soluble or dispersible products are thereby obtained.
  • lower alkyl halides such as methyl, ethyl, propyl, and butyl chlorides, bromides and iodides
  • dialkyl sulfates like dimethyl, diethyl, dibutyl and diamyl sulfates
  • long chain halides such as decyl
  • acids which can be employed to form pharmaceutically acceptable acid addition salts include such inorganic acids as hydrochloric acid, hydrobromic acid, sulphuric acid and phosphoric acid and such organic acids as oxalic acid, maleic acid, succinic acid and citric acid.
  • Basic addition salts can be prepared in situ during the final isolation and purification of compounds of this invention by reacting a carboxylic acid-containing moiety with a suitable base such as the hydroxide, carbonate or bicarbonate of a pharmaceutically acceptable metal cation or with ammonia or an organic primary, secondary or tertiary amine.
  • a suitable base such as the hydroxide, carbonate or bicarbonate of a pharmaceutically acceptable metal cation or with ammonia or an organic primary, secondary or tertiary amine.
  • Pharmaceutically acceptable salts include, but are not limited to, cations based on alkali metals or alkaline earth metals such as lithium, sodium, potassium, calcium, magnesium and aluminum salts and the like and nontoxic quaternary ammonia and amine cations including ammonium, tetramethylammonium, tetraethylammonium, methylammonium, dimethylammonium, trimethylammonium, triethylammonium, diethylammonium, and ethylammonium among others.
  • Other representative organic amines useful for the formation of base addition salts include ethylenediamine, ethanolamine, diethanolamine, piperidine, piperazine and the like.
  • Dosage forms for topical administration of a compound of this invention include powders, sprays, ointments and inhalants.
  • the active compound is mixed under sterile conditions with a pharmaceutically acceptable carrier and any needed preservatives, buffers or propellants which can be required.
  • Opthalmic formulations, eye ointments, powders and solutions are also contemplated as being within the scope of this invention.
  • Actual dosage levels of active ingredients in the pharmaceutical compositions of this invention can be varied so as to obtain an amount of the active compound(s) which is effective to achieve the desired therapeutic response for a particular patient, compositions and mode of administration.
  • the selected dosage level will depend upon the activity of the particular compound, the route of administration, the severity of the condition being treated and the condition and prior medical history of the patient being treated. However, it is within the skill of the art to start doses of the compound at levels lower than required to achieve the desired therapeutic effect and to gradually increase the dosage until the desired effect is achieved.
  • a therapeutically effective amount of one of the compounds of the present invention can be employed in pure form or, where such forms exist, in pharmaceutically acceptable salt, ester or prodrug form.
  • the compound can be administered as a pharmaceutical composition containing the compound of interest in combination with one or more pharmaceutically acceptable excipients.
  • therapeutically effective amount means a sufficient amount of the compound to treat disorders, at a reasonable benefit/risk ratio applicable to any medical treatment. It will be understood, however, that the total daily usage of the compounds and compositions of the present invention will be decided by the attending physician within the scope of sound medical judgement.
  • the specific therapeutically effective dose level for any particular patient will depend upon a variety of factors including the disorder being treated and the severity of the disorder; activity of the specific compound employed; the specific composition employed; the age, body weight, general health, sex and diet of the patient; the time of administration, route of administration, and rate of excretion of the specific compound employed; the duration of the treatment; drugs used in combination or coincidental with the specific compound employed; and like factors well known in the medical arts. For example, it is well within the skill of the art to start doses of the compound at levels lower than required to achieve the desired therapeutic effect and to gradually increase the dosage until the desired effect is achieved.
  • the total daily dose of the compounds of this invention administered to a human or lower animal may range from about 0.0001 to about 1000 mg/kg/day.
  • more preferable doses can be in the range of from about 0.001 to about 5 mg/kg/day.
  • the effective daily dose can be divided into multiple doses for purposes of administration; consequently, single dose compositions may contain such amounts or submultiples thereof to make up the daily dose.
  • the present invention also provides pharmaceutical compositions that comprise compounds of the present invention formulated together with one or more non-toxic pharmaceutically acceptable carriers.
  • the pharmaceutical compositions can be specially formulated for oral administration in solid or liquid form, for parenteral injection or for rectal administration.
  • compositions of this invention can be administered to humans and other mammals orally, rectally, parenterally, intracisternally, intravaginally, intraperitoneally, topically (as by powders, ointments or drops), bucally or as an oral or nasal spray.
  • parenterally refers to modes of administration which include intravenous, intramuscular, intraperitoneal, intrasternal, subcutaneous and intraarticular injection and infusion.
  • the present invention provides a pharmaceutical composition comprising a component of the present invention and a physiologically tolerable diluent.
  • the present invention includes one or more compounds as described above formulated into compositions together with one or more non-toxic physiologically tolerable or acceptable diluents, carriers, adjuvants or vehicles that are collectively referred to herein as diluents, for parenteral injection, for intranasal delivery, for oral administration in solid or liquid form, for rectal or topical administration, or the like.
  • compositions can also be delivered through a catheter for local delivery at a target site, via an intracoronary stent (a tubular device composed of a fine wire mesh), or via a biodegradable polymer.
  • the compounds may also be complexed to ligands, such as antibodies, for targeted delivery.
  • compositions suitable for parenteral injection may comprise physiologically acceptable, sterile aqueous or nonaqueous solutions, dispersions, suspensions or emulsions and sterile powders for reconstitution into sterile injectable solutions or dispersions.
  • suitable aqueous and nonaqueous carriers, diluents, solvents or vehicles include water, ethanol, polyols (propyleneglycol, polyethyleneglycol, glycerol, and the like), vegetable oils (such as olive oil), injectable organic esters such as ethyl oleate, and suitable mixtures thereof.
  • compositions can also contain adjuvants such as preserving, wetting, emulsifying, and dispensing agents.
  • adjuvants such as preserving, wetting, emulsifying, and dispensing agents.
  • Prevention of the action of microorganisms can be ensured by various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, sorbic acid, and the like. It may also be desirable to include isotonic agents, for example sugars, sodium chloride and the like.
  • Prolonged absorption of the injectable pharmaceutical form can be brought about by the use of agents delaying absorption, for example, aluminum monostearate and gelatin.
  • Suspensions in addition to the active compounds, may contain suspending agents, as for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar-agar and tragacanth, or mixtures of these substances, and the like.
  • suspending agents as for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar-agar and tragacanth, or mixtures of these substances, and the like.
  • Proper fluidity can be maintained, for example, by the use of coating materials such as lecithin, by the maintenance of the required particle size in the case of dispersions and by the use of surfactants.
  • delayed absorption of a parenterally administered drug form is accomplished by dissolving or suspending the drug in an oil vehicle.
  • Injectable depot forms are made by forming microencapsule matrices of the drug in biodegradable polymers such as polylactide-polyglycolide. Depending upon the ratio of drug to polymer and the nature of the particular polymer employed, the rate of drug release can be controlled. Examples of other biodegradable polymers include poly(orthoesters) and poly(anhydrides). Depot injectable formulations are also prepared by entrapping the drug in liposomes or microemulsions which are compatible with body tissues.
  • Solid dosage forms for oral administration include capsules, tablets, pills, powders and granules.
  • the active compound may be mixed with at least one inert, pharmaceutically acceptable excipient or carrier, such as sodium citrate or dicalcium phosphate and/or a) fillers or extenders such as starches, lactose, sucrose, glucose, mannitol and silicic acid; b) binders such as carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidone, sucrose and acacia; c) humectants such as glycerol; d) disintegrating agents such as agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates and sodium carbonate; e) solution retarding agents such as paraffin; f) absorption accelerators such as quaternary ammonium compounds; g) wetting agents such as cetyl alcohol and glycerol monostearate; h)
  • Solid compositions of a similar type may also be employed as fillers in soft and hard-filled gelatin capsules using such excipients as lactose or milk sugar as well as high molecular weight polyethylene glycols and the like.
  • the solid dosage forms of tablets, dragees, capsules, pills and granules can be prepared with coatings and shells such as enteric coatings and other coatings well-known in the pharmaceutical formulating art. They may optionally contain opacifying agents and may also be of a composition such that they release the active ingredient(s) only, or preferentially, in a certain part of the intestinal tract, optionally, in a delayed manner.
  • Examples of embedding compositions which can be used include polymeric substances and waxes.
  • the active compounds can also be in micro-encapsulated form, if appropriate, with one or more of the above-mentioned excipients.
  • Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups and elixirs.
  • the liquid dosage forms may contain inert diluents commonly used in the art such as, for example, water or other solvents, solubilizing agents and emulsifiers such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimethyl formamide, oils (in particular, cottonseed, groundnut, corn, germ, olive, castor and sesame oils), glycerol, tetrahydrofurfuryl alcohol, polyethylene glycols and fatty acid esters of sorbitan and mixtures thereof.
  • inert diluents commonly used in the art such as, for example, water or other solvents, solubilizing agents and emulsifiers such as
  • the oral compositions may also include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring and perfuming agents.
  • adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring and perfuming agents.
  • compositions for rectal or vaginal administration are preferably suppositories which can be prepared by mixing the compounds of this invention with suitable non-irritating excipients or carriers such as cocoa butter, polyethylene glycol or a suppository wax which are solid at room temperature but liquid at body temperature and therefore melt in the rectum or vaginal cavity and release the active compound.
  • suitable non-irritating excipients or carriers such as cocoa butter, polyethylene glycol or a suppository wax which are solid at room temperature but liquid at body temperature and therefore melt in the rectum or vaginal cavity and release the active compound.
  • Liposomes are generally derived from phospholipids or other lipid substances. Liposomes are formed by mono-or multi-lamellar hydrated liquid crystals which are dispersed in an aqueous medium. Any non-toxic, physiologically acceptable and metabolizable lipid capable of forming liposomes can be used.
  • the present compositions in liposome form can contain, in addition to a compound of the present invention, stabilizers, preservatives, excipients and the like.
  • the preferred lipids are natural and synthetic phospholipids and phosphatidyl cholines (lecithins) used separately or together.
  • Stereoisomers include enantiomers and diastereomers, and mixtures of enantiomers or diastereomers.
  • Individual stereoisomers of compounds of the present invention may be prepared synthetically from commercially available starting materials which contain asymmetric or chiral centers or by preparation of racemic mixtures followed by resolution well-known to those of ordinary skill in the art.
  • a cell expressing ⁇ 4 ⁇ 1 integrin can be a naturally occurring white blood cell, mast cell or other cell type that naturally expresses ⁇ 4 ⁇ 1 on the cell surface, or a cell transfected with an expression vector that contains a poly-nucleotide (e.g., genomic DNA or cDNA) that encodes ⁇ 4 ⁇ 1 integrin.
  • ⁇ 4 ⁇ 1 integrin is present on the surface of a white blood cell such as a monocyte, a lymphocyte or a granulocyte (e.g., an eosinophil or a basophil).
  • a cell that expresses VCAM-1 can be a naturally occurring cell (e.g. an endothelial cell) or a cell transfected with an expression vector containing a polynucleotide that encodes VCAM-1. Methods for producing transfected cells that express VCAM-1 are well known in the art.
  • VCAM-1 exists on the surface of cell
  • the expression of that VCAM-1 is preferably induced by inflammatory cytokines such as tumor necrosis factor- ⁇ , interleukin-4 and interleukin-1 ⁇ .
  • a compound of the present invention is administered in an effective amount to the living organism.
  • the compound is in a pharmaceutical composition of this invention.
  • the compounds and compositions of the present invention are used for manufacturing medicaments for selected from the group consisting of asthma, atherosclerosis, rheumatoid arthritis, allergy, multiple sclerosis, lupus, inflammatory bowel disease, graft rejection, contact hypersensitivity, type I diabetes, leukemia, and brain cancer.
  • Administration is preferably accomplished via intravascular, subcutaneous, intranasal, transdermal or oral delivery.
  • the compounds of the present invention are suitable for selectively inhibiting the binding of ⁇ 4 ⁇ 1 integrin to a protein comprising exposing the integrin to the protein in the presence of an effective inhibiting amount of a compound of the present invention.
  • the ⁇ 4 ⁇ 1 integrin is expressed on the surface of a cell, either naturally occurring or a cell transformed to express ⁇ 4 ⁇ 1 integrin.
  • the protein to which the ⁇ 4 ⁇ 1 integrin binds can be expressed either on a cell surface or be part of the extracellular matrix.
  • Especially preferred proteins are fibronectin or invasin.
  • Compound 15 (3 S )-3-(1,3-benzodioxol-5-yl)-3-((2 R,S )-2-(3-(4-methoxybenzyl)-5-methyl-2-oxo-1(2 H )-pyridinyl)hexanoylamino)propanoic acid, shown below, can be obtained by the procedure of Example 1, except that 3-(4-methoxyphenyl)-propanoyl chloride should be substituted for 3-phenylpropanoyl chloride in step 2.
  • Compound 16 (3 S )-3-(1,3-benzodioxol-5-yl)-3-((2 R,S )-2-(3-(4-methylbenzyl)-5-methyl-2-oxo-1(2 H )-pyridinyl)hexanoylamino)propanoic acid, shown below can be obtained by the procedure of Example 1, except that 3-(4-methylphenyl)-propanoyl chloride should be substituted for 3-phenylpropanoyl chloride in step 2.
  • (3S)-3-(1,3-benzodioxol-5-yl)-3-( ⁇ 2-[5,5-dimethyl-2,4-dioxo-3-(phenylmethyl)tetrahydro-1H-imidazol-1-yl]hexanoyl ⁇ amino)propanoic acid was prepared from 53 according to procedures described in Examples 1 and 16. MP: 53-55 °C.
  • (3S)-3-(1,3-benzodioxol-5-yl)-3-( ⁇ 2-[3-methyl-6-oxo-5-(phenylmethyl)-1(6H)-pyridazinyl]hexanoyl ⁇ amino)propanoic acid was prepared from 56 according to procedures described in Examples 1 and 16.
  • (3S)-3-(1,3-benzodioxol-5-yl)-3-( ⁇ 2-[2-oxo-3-(phenylmethyl)-3,4-dihydro-1(2H)-quinazolinyl]hexanoyl ⁇ amino)propanoic acid was prepared with 57 according to procedures described in Examples 1 and 16.
  • the ability of compounds of the present invention to inhibit binding is determined by a procedure in which a 26-amino acid peptide containing the CS 1 sequence of fibronectin with an N-terminal Cys (CDELPQLVTLPHPNLHGPEILDVPST) was coupled to maleimide activated ovalbumin.
  • Bovine serum albumin (BSA) and CS 1 conjugated ovalbumin were coated onto 96-well polystyrene plates at 0.5 mg/ml in TBS (50 mM Tris, pH 7.5; 150 mM NaCl) at 4°C for 16 hours. The plates were washed three times with TBS and blocked with TBS containing 3% BSA at room temperature for 4 hours.
  • Blocked plates were washed three times in binding buffer (TBS; 1 mM MgCl 2 ; 1 mM CaCl 2 ; 1 mM MnCl 2 ) prior to assay.
  • Ramos cells fluorescently labeled with calcein AM were resuspended in binding buffer (10 7 cells/ml) and diluted 1:2 with same buffer with or without compound. The cells were added immediately to the wells (2.5 x 10 5 cells/well) and incubated for 30 minutes at 37°C. Following three washes with binding buffer, adherent cells were lysed and quantitated using a fluorometer. The results are shown in Tables 1, 2, 3 and 4. IC 50 is defined as the dose required to give 50% inhibition. MS in Table 3 stands for Mass Spec.
  • nd stands for not determined in the Tables.
  • A stands for inhibition in Table 2, and the percent inhibition indicates the inhibition of cell adhesion when compound is included in the assay at a concentration of 100 [ ⁇ M. The lower the IC 50 value and the greater the percentage of inhibition, the more efficient the compound is at prevention of cell adhesion.

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Abstract

A method for the inhibition of the binding of alpha 4 beta 1 integrin to its receptors, for example VCAM-1 (vascular cell adhesion molecule-1) and fibronectin; compounds (I) that inhibit this binding; pharmaceutically active compositions comprising such compounds; and the use of such compounds either as above, or in formulations for the control or prevention of diseases states in which alpha 4 beta 1 is involved. <CHEM> All substituents are as defined in the application.g

Description

    Field of the Invention
  • This invention is directed generally to the inhibition of the binding of α4β1 integrin to its receptors, for example VCAM-1 (vascular cell adhesion molecule-1) and fibronectin. The invention also relates to compounds that inhibit this binding, to pharmaceutically active compositions comprising such compounds and to the use of such compounds either as above, or in formulations for the control or prevention of disease states in which α4β1 is involved.
    • Background of the Invention
  • When a tissue has been invaded by a microorganism or has been damaged, white blood cells, also called leukocytes, play a major role in the inflammatory response. One of the most important aspects of the inflammatory response involves the cell adhesion event. Generally, white blood cells are found circulating through the bloodstream. However, when a tissue is infected or becomes damaged, the white blood cells recognize the invaded or damage tissue, bind to the wall of the capillary and migrate through the capillary into the affected tissue. These events are mediated by a family of proteins called cell adhesion molecules.
  • There are three main types of white blood cells: granulocytes, monocytes and lymphocytes. The integrin α4β1 (also called VLA-4 for very late-antigen-4) is a heterodimeric protein expressed on the surface of monocytes, lymphocytes and two subclasses of granulocytes: eosinophils and basophils. This protein plays a key role in cell adhesion through its ability to recognize and bind VCAM-1 and fibronectin, proteins associated with the endothelial cells that line the interior wall of capillaries.
  • Following infection or damage of tissue surrounding a capillary, endothelial cells express a series of adhesion molecules, including VCAM-1, that are critical for binding the white blood cells that are necessary for fighting infection. Prior to binding to VCAM-1 or fibronectin, the white blood cells initially bind to certain adhesion molecules to slow their flow and allow the cells to "roll" along the activated endothelium. Monocytes, lymphocytes, basophils and eosinophils are then able to firmly bind to VCAM-1 or fibronectin on the blood vessel wall via the α4β1 integrin. There is evidence that such interactions are also involved in transmigration of these white blood cells into the damaged tissue, as well as the initial rolling event itself.
  • Although white blood cell migration to the site of injury helps fight infection and destroy foreign material, in many instances this migration can become uncontrolled, with white blood cells flooding to the scene, causing widespread tissue damage. Compounds capable of blocking this process, therefore, may be beneficial as therapeutic agents. Thus, it would be useful to develop inhibitors that would prevent the binding of white blood cells to VCAM-1 and fibronectin.
  • Some of the diseases that might be treated by the inhibition of α4β1 binding include, but are not limited to, atherosclerosis, rheumatoid arthritis, asthma, allergy, multiple sclerosis, lupus, inflammatory bowel disease, graft rejection, contact hypersensitivity, and type I diabetes. In addition to being found on some white blood cells, α4β1 is also found on various cancer cells, including leukemia, melanoma, lymphoma and sarcoma cells. It has been suggested that cell adhesion involving α4β1 may be involved in the metastasis of certain cancers. Inhibitors of α4β1 binding may, therefore, also be useful in the treatment of some forms of cancer.
  • The isolation and purification of a peptide which inhibits the binding of α4β1 to a protein is disclosed in U.S. Patent No. 5,510,332 . Peptides which inhibit binding are disclosed in WO 95/15973 , EP 0 341 915 , EP 0 422 938 A1 , U.S. Patent No. 5,192,746 and WO 96/06108 . Novel compounds which are useful for inhibition and prevention of cell adhesion and cell adhesion-mediated pathologies are disclosed in WO 96/22966 , WO 98/04247 and WO 98/04913 .
  • WO 99/52943 describes a method for expressing T cell receptors and suitable vectors. Also disclosed are cells that are transfected with these vectors and express the desired T cell receptors.
  • EP 512831 discloses substituted amides as fibrinogen receptor antagonists useful for inhibition of binding of fibrinogen to blood platelets and inhibition of their aggregation.
  • WO 9804247 discloses amide derivatives as inhibitors of integrins, in particular, integrins of α4β1 and αIIbβIIIa subfamilies.
  • Egbertson et al., Bioorganic & Medicinal Chemistry Letters, 10 (2000) 1943-48, disclose non-peptide amide derivatives as selective antagonists of IIb/IIIa integrin receptors. It was demonstrated that the selectivity of the compounds depends on their structure: compounds containing a C6 flexible region and an amide bond of the correct orientation are more selective inhibitors than those possessing a C6 constrained region.
  • It is therefore an object of the invention to provide novel compounds which are inhibitors of α4β1 binding, and pharmaceutical compositions including such novel compounds.
    • Brief Summary of the Invention
  • The invention is directed to novel compounds selected from the group consisting of (3S)-3- {[(2S)-2-(3-benzyl-5-methyl-2-oxopyridin-1 (2H)-yl)hexanoyl]amino} -3-(3',4'-dimethoxy-1,1'-biphenyl-4-yl)propanoic acid, (3S)-3-({(2S)-2-[3-(2-chlorobenzyl)-5-methyl-2-oxopyridin-1 (2H)-yl]hexanoyl} amino)-3-(3',4'-dimethoxy-1,1'-biphenyl-4-yl)propanoic acid, (3S)-3-(1,1'-biphenyl-4-yl)-3-({(2S)-2-[3-(2-chloro-6-methylbenzyl)-5-methyl-2-oxopyridin-1(2H)-yl]hexanoyl}amino)propanoic acid, (3S)-3-{[(2S)-2-(3-benzyl-5-methyl-2-oxopyridin-1(2H)-yl)hexanoyl]amino}-3-(1,1'-biphenyl-4-yl)propanoic acid, (3S)-3-(1,1'-biphenyl-4-yl)-3-({(2S)-2-[3-(2-chlorobenzyl)-5-methyl-2-oxopyridin-1(2H)-yl]hexanoyl}amino)propanoic acid, (3S)-3-{[(2S)-2-(3-benzyl-5-methyl-2-oxopyridin- (2H)-yl)hexanoyl]amino}-3-(4'-methyl-1,1'-biphenyl-4-yl)propanoic acid, (3S)-3-({(2S)-2-[3-(2-chlorobenzyl)-5-methyl-2-oxopyridin-1(2H)-yl]hexanoyl}amino)-3-(4'-methyl-1,1'-biphenyl-4-yl)propanoic acid, (3S)-3-({(2S)-2-[3-(2-chloro-6-methylbenzyl)-5-methyl-2-oxopyridin-1(2H)-yl]hexanoyl}amino)-3-(4'-methyl-1,1'-biphenyl-4-yl)propanoic acid, (35)-3-{[(2S)-2-(3-benzyl-5-methyl-2-oxopyridin-1(2H)-yl)hexanoyl]amino}-3-(2',6'-dimethoxy-1,1'-biphenyl-4-yl)propanoic acid, (3S)-3-({(2S)-2-[3-(2-chlorobenzyl)-5-methyl-2-oxopyridin-1 (2H)-yl]hexanoyl}amino)-3-(2',6'-dimethoxy-1,1'-biphenyl-4-yl)propanoic acid, (3S)-3-({(25)-2-[3-(2-chloro-6-methylbenzyl)-5-methyl-2-oxopyridin- (2H)-yl]hexanoyl}amino)-3-(2',6'-dimethoxy-1,1'-biphenyl-4-yl)propanoic acid, (3S)-3- {[(2S)-2-(3-benzyl-5-methyl-2-oxopyridin-1(2H)-yl)hexanoyl]amino}-3-(1,1'-biphenyl-3-yl)propanoic acid, (3S)-3-(1,1'-biphenyl-3-yl)-3-({(2S)-2-[3-(2-chlorobenzyl)-5-methyl-2-oxopyridin-1(2H)-yl]hexanoyl}amino)propanoic acid, (3S)-3-(1,1'-biphenyl-3-yl)-3-({(2S)-2-[3-(2-chloro-6-methylbenzyl)-5-methyl-2-oxopyridin-1(2H)-yl]hexanoyl}amino)propanoic acid, (3S)-3-{[(2S)-2-(3-benzyl-5-methyl-2-oxopyridin-1(2H)-yl)hexanoyl]amino}-3-(2'-methoxy-1,1'-biphenyl-3-yl)propanoic acid, (3S)-3-({(2S)-2-[3-(2-chlorobenzyl)-5-methyl-2-oxopyridin-1 (2H)-yl]hexanoyl}amino)-3-(2'-methoxy-1,1'-biphenyl-3-yl)propanoic acid, (3S)-3-({(2S)-2-[3-(2-chloro-6-methylbenzyl)-5-methyl-2-oxopyridin-1(2H)-yl]hexanoyl}amino)-3-(2'-methoxy-1,1'-biphenyl-3-yl)propanoic acid, (3S)-3-({(2S)-2-[3-(2-fluoro-6-methoxybenzyl)-5-methyl-2-oxopyridin- 1(2H)-yl]hexanoyl}amino)-3-(4-methylphenyl)propanoic acid, (3S)-3-({(2S)-2-[3-(2,6-dimethylbenzyl)-5-methyl-2-oxopyridin-1(2H)-yl]hexanoyl}amino)-3-(4-methylphenyl)propanoic acid, (3S)-3-({(2S)-2-[3-(3,5-dimethylbenzyl)-5-methyl-2-oxopyridin-1 (2H)-yl]hexanoyl}amino)-3-(4-methylphenyl)propanoic acid, (3S)-3-({(2S)-2-[3-(2,6-dichlorobenzyl)-5-methyl-2-oxopyridin- (2H)-yl]hexanoyl}amino)-3-(4-methylphenyl)propanoic acid, (3S)-3-({(2S)-2-[3-(2-chloro-6-fluorobenzyl)-5-methyl-2-oxopyridin-1(2H)-yl]hexanoyl}amino)-3-(4-methylphenyl)propanoic acid, (3S)-3-({(2S)-2-[3-(2,6-difluorobenzyl)-5-methyl-2-oxopyridin-1(2H)-yl]hexanoyl}amino)-3-(4-methylphenyl)propanoic acid, (3S)-3-(1,3-benzodioxol-5-yl)-3-({(2S)-2-[3-(2,6-difluorobenzyl)-5-methyl-2-oxopyridin-1(2H)-yl]hexanoyl}amino)propanoic acid, (3S)-3-(1,3-benzodioxol-5-yl)-3-({(2S)-2-[3-(2-chloro-6-fluorobenzyl)-5-methyl-2-oxopyridin-1(2H)-yl]hexanoyl}amino)propanoic acid, (3S)-3-(1,3-benzodioxol-5-yl)-3-({(2S)-2-[3-(2,6-dichlorobenzyl)-5-methyl-2-oxopyridin-1(2H)-yl]hexanoyl}amino)propanoic acid, (3S)-3-(1,3-benzodioxol-5-yl)-3-({(2S)-2-[3-(2,6-dimethylbenzyl)-5-methyl-2-oxopyridin-1(2H)-yl]hexanoyl}amino)propanoic acid, (3S)-3-(1,3-benzodioxol-5-yl)-3-({(2S)-2-[3-(3,5-dimethylbenzyl)-5-methyl-2-oxopyridin-1(2H)-yl]hexanoyl}amino)propanoic acid, (3S)-3-(1,3-benzodioxol-5-yl)-3-({(2S)-2-[3-(2-fluoro-6-methoxybenzyl)-5-methyl-2-oxopyridin-1 (2H)-yl]hexanoyl}amino)propanoic acid, (3S)-3-({(2S)-2-[3-(2-chlorobenzyl)-5-methyl-2-oxopyridin- (2H)-yl]hexanoyl }amino)-3-(3,4-diethoxyphenyl)propanoic acid, (3S)-3-(3,4-diethoxyphenyl)-3-({(2S)-2-[3-(2,6-difluorobenzyl)-5-methyl-2-oxopyridin- (2H)-yl]hexanoyl} amino)propanoic acid, (3S)-3-({(2S)-2-[3-(2,6-difluorobenzyl)-5-methyl-2-oxopyridin-1(2H)-yl]hexanoyl}amino)-3-(3-ethoxyphenyl)propanoic acid, (3S)-3-({(2S)-2-[3-(2-chloro-6-fluorobenzyl)-5-methyl-2-oxopyridin-1(2H)-yl]hexanoyl}amino)-3-(3-ethoxyphenyl)propanoic acid, (3S)-3-( {(2S)-2-[3-(2-chlorobenzyl)-5-methyl-2-oxopyridin-1(2H)-yl]-3-methylbutanoyl}amino)-3-(4-methylphenyl)propanoic acid, (3S)-3-({(2S)-2-[3-(2-chlorobenzyl)-5-methyl-2-oxopyridin-1(2H)-yl]-4-methylpentanoyl}amino)-3-(4-methylphenyl)propanoic acid, (3S)-3-(1,3-benzodioxol-5-yl)-3-({(2S)-2-[3-(2-chlorobenzyl)-5-methyl-2-oxopyridin-1(2H)-yl]-4-methylpentanoyl}amino)propanoic acid, (3S)-3-(1,3-benzodioxol-5-yl)-3-({(2S)-2-[3-(2-chlorobenzyl)-5-methyl-2-oxopyridin- (2H)-yl]-3-methylbutanoyl}amino)propanoic acid, (3S)-3-(1,3-benzodioxol-5-yl)-3-({(2S)-2-[3-(2-chlorobenzyl)-5-methyl-2-oxopyridin-1(2H)-yl]-3-phenylpropanoyl}amino)propanoic acid, (3S)-3-({(2S)-2-[3-(2-chlorobenzyl)-5-methyl-2-oxopyridin-1(2H)-yl]-3-phenylpropanoyl}amino)-3-(4-methylphenyl)propanoic acid, (3S)-3-(1,3-benzodioxol-5-yl)-3-(((2R)-2-(1-benzyl-5-methyl-2-oxo-1,2-dihydropyridin-3-yl)hexanoyl)amino) propanoic acid and pharmaceutically acceptable salts thereof.
  • A presently most preferred compound is (3S)-3-(1,3-benzodioxol-5-yl)-3-((2S)-2-(3-benzyl-5-methyl-2-oxo-1(2H)-pyridinyl)hexanoyl)amino)propanoic acid or a pharmaceutically acceptable salt thereof.
  • The present invention also relates to pharmaceutical compositions comprising a physiologically acceptable diluent and at least one compound of the present invention.
  • The present invention further relates to the use of a compound of the invention for manufacturing a medicament for treating a disease selected from the group consisting of asthma, atherosclerosis, rheumatoid arthritis, allergy, multiple sclerosis, lupus, inflammatory bowel disease, graft rejection, contact hypersensitivity, type I diabetes, leukaemia, and brain cancer.
  • The invention further relates to a compound of the invention for use as a medicament.
    • Detailed Description of the Invention Abbreviations
  • Abbreviations which have been used in the schemes and the examples which follow are: BOC for t-butyloxycarbonyl; EtOAc for ethyl acetate; DMF for dimethylformamide; THF for tetrahydrofuran; Tos for p-toluenesulfonyl; DCC for dicyclohexylcarbodiimide; HOBT for 1-hydroxybenzotriazole; TFAA for trifluoroacetic anhydride; NMM for N-methyl morpholine; DIPEA for diisopropylethylamine; DCM for methylene dichloride; LHMDS for lithium hexamethyl disilazide; NaHMDS for sodium hexamethyl disilazide; CDI for 1,1'-carbonyldiimidazole HBTU for O-benzotriazol-1-yl-N,N,N', N'-tetramethyluronium hexafluorophosphate, EDCI for 1-[3-(dimethylamino) propyl]-3-ethylcarbodiimide hydrochloride and TBS for TRIS-buffered saline. Amino acids are abbreviated as follows: C for L-cysteine; D for L-aspartic acid; E for L-glutamic acid; G for glycine; H for L-histidine; I for L-isoleucine; L for L-leucine; N for L-asparagine; P for L-proline; Q for L-glutamine; S for L-serine; T for L-threonine; V for L-valine, and W for L-tryptophan.
  • Examples of the procedures utilized to synthesize the compounds are illustrated by the following schemes.
    Figure imgb0001
    Figure imgb0002
    • Scheme 3, shown below, illustrates the procedure described in Example 11.
  • Figure imgb0003
    • Scheme 4, shown below, illustrates Example 12.
  • Figure imgb0004
    • Scheme 5, shown below, illustrates the procedure of Example 13.
  • Figure imgb0005
    • Scheme 6, shown below, illustrates the procedure described in Example 14.
  • Figure imgb0006
    • Scheme 7, shown below, illustrates the procedure described in Example 15.
  • Figure imgb0007
    • Scheme 8, shown below, illustrates the procedure described in Example 16.
  • Figure imgb0008
    • Scheme 9, shown below, illustrates the procedure described in Example 17.
  • Figure imgb0009
    • Scheme 10, shown below, illustrates the procedure described in Example 18.
  • Figure imgb0010
    • Scheme 11, shown below, illustrates the procedure described in Example 19.
  • Figure imgb0011
    • Scheme 12, shown below, illustrates the procedure described in Example 20.
  • Figure imgb0012
    • Scheme 13, shown below, illustrates the procedure described in Example 21.
  • Figure imgb0013
    • Scheme 14, shown below, illustrates the procedure of Example 22.
  • Figure imgb0014
    Figure imgb0015
    Figure imgb0016
    Figure imgb0017
  • A detailed description of the preparation of representative compounds of the present invention is set forth in the Examples.
  • The compounds of the present invention can be used in the form of pharmaceutically acceptable salts derived from inorganic or organic acids. The phrase "pharmaceutically acceptable salt" means those salts which are, within the scope of sound medical judgement, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response and the like and are commensurate with a reasonable benefit/risk ratio. Pharmaceutically acceptable salts are well-known in the art. For example, S. M. Berge et al. describe pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences, 1977, 66: 1 et seq. The salts can be prepared in situ during the final isolation and purification of the compounds of the invention or separately by reacting a free base function with a suitable organic acid. Representative acid addition salts include, but are not limited to acetate, adipate, alginate, citrate, aspartate, benzoate, benzene sulfonate, bisulfate, butyrate, camphorate, camphor sulfonate, digluconate, glycerophosphate, hemisulfate, heptanoate, hexanoate, fumarate, hydrochloride, hydrobromide, hydroiodide, 2-hydroxyethansulfonate (isothionate), lactate, maleate, methane sulfonate, nicotinate, 2-naphthalene sulfonate, oxalate, palmitoate, pectinate, persulfate, 3-phenylpropionate, picrate, pivalate, propionate, succinate, tartrate, thiocyanate, phosphate, glutamate, bicarbonate, p-toluene sulfonate and undecanoate. Also, the basic nitrogen-containing groups can be quatemized with such agents as lower alkyl halides such as methyl, ethyl, propyl, and butyl chlorides, bromides and iodides; dialkyl sulfates like dimethyl, diethyl, dibutyl and diamyl sulfates; long chain halides such as decyl, lauryl, myristyl and stearyl chlorides, bromides and iodides; arylalkyl halides like benzyl and phenethyl bromides and others. Water or oil-soluble or dispersible products are thereby obtained. Examples of acids which can be employed to form pharmaceutically acceptable acid addition salts include such inorganic acids as hydrochloric acid, hydrobromic acid, sulphuric acid and phosphoric acid and such organic acids as oxalic acid, maleic acid, succinic acid and citric acid.
  • Basic addition salts can be prepared in situ during the final isolation and purification of compounds of this invention by reacting a carboxylic acid-containing moiety with a suitable base such as the hydroxide, carbonate or bicarbonate of a pharmaceutically acceptable metal cation or with ammonia or an organic primary, secondary or tertiary amine. Pharmaceutically acceptable salts include, but are not limited to, cations based on alkali metals or alkaline earth metals such as lithium, sodium, potassium, calcium, magnesium and aluminum salts and the like and nontoxic quaternary ammonia and amine cations including ammonium, tetramethylammonium, tetraethylammonium, methylammonium, dimethylammonium, trimethylammonium, triethylammonium, diethylammonium, and ethylammonium among others. Other representative organic amines useful for the formation of base addition salts include ethylenediamine, ethanolamine, diethanolamine, piperidine, piperazine and the like.
  • Dosage forms for topical administration of a compound of this invention include powders, sprays, ointments and inhalants. The active compound is mixed under sterile conditions with a pharmaceutically acceptable carrier and any needed preservatives, buffers or propellants which can be required. Opthalmic formulations, eye ointments, powders and solutions are also contemplated as being within the scope of this invention.
  • Actual dosage levels of active ingredients in the pharmaceutical compositions of this invention can be varied so as to obtain an amount of the active compound(s) which is effective to achieve the desired therapeutic response for a particular patient, compositions and mode of administration. The selected dosage level will depend upon the activity of the particular compound, the route of administration, the severity of the condition being treated and the condition and prior medical history of the patient being treated. However, it is within the skill of the art to start doses of the compound at levels lower than required to achieve the desired therapeutic effect and to gradually increase the dosage until the desired effect is achieved.
  • When used in the above or other treatments, a therapeutically effective amount of one of the compounds of the present invention can be employed in pure form or, where such forms exist, in pharmaceutically acceptable salt, ester or prodrug form. Alternatively, the compound can be administered as a pharmaceutical composition containing the compound of interest in combination with one or more pharmaceutically acceptable excipients. The phrase "therapeutically effective amount" of the compound of the invention means a sufficient amount of the compound to treat disorders, at a reasonable benefit/risk ratio applicable to any medical treatment. It will be understood, however, that the total daily usage of the compounds and compositions of the present invention will be decided by the attending physician within the scope of sound medical judgement. The specific therapeutically effective dose level for any particular patient will depend upon a variety of factors including the disorder being treated and the severity of the disorder; activity of the specific compound employed; the specific composition employed; the age, body weight, general health, sex and diet of the patient; the time of administration, route of administration, and rate of excretion of the specific compound employed; the duration of the treatment; drugs used in combination or coincidental with the specific compound employed; and like factors well known in the medical arts. For example, it is well within the skill of the art to start doses of the compound at levels lower than required to achieve the desired therapeutic effect and to gradually increase the dosage until the desired effect is achieved.
  • The total daily dose of the compounds of this invention administered to a human or lower animal may range from about 0.0001 to about 1000 mg/kg/day. For purposes of oral administration, more preferable doses can be in the range of from about 0.001 to about 5 mg/kg/day. If desired, the effective daily dose can be divided into multiple doses for purposes of administration; consequently, single dose compositions may contain such amounts or submultiples thereof to make up the daily dose.
  • The present invention also provides pharmaceutical compositions that comprise compounds of the present invention formulated together with one or more non-toxic pharmaceutically acceptable carriers. The pharmaceutical compositions can be specially formulated for oral administration in solid or liquid form, for parenteral injection or for rectal administration.
  • The pharmaceutical compositions of this invention can be administered to humans and other mammals orally, rectally, parenterally, intracisternally, intravaginally, intraperitoneally, topically (as by powders, ointments or drops), bucally or as an oral or nasal spray. The term "parenterally," as used herein, refers to modes of administration which include intravenous, intramuscular, intraperitoneal, intrasternal, subcutaneous and intraarticular injection and infusion.
  • In another aspect, the present invention provides a pharmaceutical composition comprising a component of the present invention and a physiologically tolerable diluent. The present invention includes one or more compounds as described above formulated into compositions together with one or more non-toxic physiologically tolerable or acceptable diluents, carriers, adjuvants or vehicles that are collectively referred to herein as diluents, for parenteral injection, for intranasal delivery, for oral administration in solid or liquid form, for rectal or topical administration, or the like.
  • The compositions can also be delivered through a catheter for local delivery at a target site, via an intracoronary stent (a tubular device composed of a fine wire mesh), or via a biodegradable polymer. The compounds may also be complexed to ligands, such as antibodies, for targeted delivery.
  • Compositions suitable for parenteral injection may comprise physiologically acceptable, sterile aqueous or nonaqueous solutions, dispersions, suspensions or emulsions and sterile powders for reconstitution into sterile injectable solutions or dispersions. Examples of suitable aqueous and nonaqueous carriers, diluents, solvents or vehicles include water, ethanol, polyols (propyleneglycol, polyethyleneglycol, glycerol, and the like), vegetable oils (such as olive oil), injectable organic esters such as ethyl oleate, and suitable mixtures thereof.
  • These compositions can also contain adjuvants such as preserving, wetting, emulsifying, and dispensing agents. Prevention of the action of microorganisms can be ensured by various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, sorbic acid, and the like. It may also be desirable to include isotonic agents, for example sugars, sodium chloride and the like. Prolonged absorption of the injectable pharmaceutical form can be brought about by the use of agents delaying absorption, for example, aluminum monostearate and gelatin.
  • Suspensions, in addition to the active compounds, may contain suspending agents, as for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar-agar and tragacanth, or mixtures of these substances, and the like.
  • Proper fluidity can be maintained, for example, by the use of coating materials such as lecithin, by the maintenance of the required particle size in the case of dispersions and by the use of surfactants. In some cases, in order to prolong the effect of the drug, it is desirable to slow the absorption of the drug from subcutaneous or intramuscular injection. This can be accomplished by the use of a liquid suspension of crystalline or amorphous material with poor water solubility. The rate of absorption of the drug then depends upon its rate of dissolution which, in turn, may depend upon crystal size and crystalline form. Alternatively, delayed absorption of a parenterally administered drug form is accomplished by dissolving or suspending the drug in an oil vehicle.
  • Injectable depot forms are made by forming microencapsule matrices of the drug in biodegradable polymers such as polylactide-polyglycolide. Depending upon the ratio of drug to polymer and the nature of the particular polymer employed, the rate of drug release can be controlled. Examples of other biodegradable polymers include poly(orthoesters) and poly(anhydrides). Depot injectable formulations are also prepared by entrapping the drug in liposomes or microemulsions which are compatible with body tissues. The injectable formulations can be sterilized, for example, by filtration through a bacterial-retaining filter or by incorporating sterilizing agents in the form of sterile solid compositions which can be dissolved or dispersed in sterile water or other sterile injectable medium just prior to use.
  • Solid dosage forms for oral administration include capsules, tablets, pills, powders and granules. In such solid dosage forms, the active compound may be mixed with at least one inert, pharmaceutically acceptable excipient or carrier, such as sodium citrate or dicalcium phosphate and/or a) fillers or extenders such as starches, lactose, sucrose, glucose, mannitol and silicic acid; b) binders such as carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidone, sucrose and acacia; c) humectants such as glycerol; d) disintegrating agents such as agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates and sodium carbonate; e) solution retarding agents such as paraffin; f) absorption accelerators such as quaternary ammonium compounds; g) wetting agents such as cetyl alcohol and glycerol monostearate; h) absorbents such as kaolin and bentonite clay and i) lubricants such as talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate and mixtures thereof. In the case of capsules, tablets and pills, the dosage form may also comprise buffering agents.
  • Solid compositions of a similar type may also be employed as fillers in soft and hard-filled gelatin capsules using such excipients as lactose or milk sugar as well as high molecular weight polyethylene glycols and the like. The solid dosage forms of tablets, dragees, capsules, pills and granules can be prepared with coatings and shells such as enteric coatings and other coatings well-known in the pharmaceutical formulating art. They may optionally contain opacifying agents and may also be of a composition such that they release the active ingredient(s) only, or preferentially, in a certain part of the intestinal tract, optionally, in a delayed manner. Examples of embedding compositions which can be used include polymeric substances and waxes.
  • The active compounds can also be in micro-encapsulated form, if appropriate, with one or more of the above-mentioned excipients.
  • Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups and elixirs. In addition to the active compounds, the liquid dosage forms may contain inert diluents commonly used in the art such as, for example, water or other solvents, solubilizing agents and emulsifiers such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimethyl formamide, oils (in particular, cottonseed, groundnut, corn, germ, olive, castor and sesame oils), glycerol, tetrahydrofurfuryl alcohol, polyethylene glycols and fatty acid esters of sorbitan and mixtures thereof.
  • Besides inert diluents, the oral compositions may also include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring and perfuming agents.
  • Compositions for rectal or vaginal administration are preferably suppositories which can be prepared by mixing the compounds of this invention with suitable non-irritating excipients or carriers such as cocoa butter, polyethylene glycol or a suppository wax which are solid at room temperature but liquid at body temperature and therefore melt in the rectum or vaginal cavity and release the active compound.
  • Compounds of the present invention can also be administered in the form of liposomes. As is known in the art, liposomes are generally derived from phospholipids or other lipid substances. Liposomes are formed by mono-or multi-lamellar hydrated liquid crystals which are dispersed in an aqueous medium. Any non-toxic, physiologically acceptable and metabolizable lipid capable of forming liposomes can be used. The present compositions in liposome form can contain, in addition to a compound of the present invention, stabilizers, preservatives, excipients and the like. The preferred lipids are natural and synthetic phospholipids and phosphatidyl cholines (lecithins) used separately or together.
  • Methods to form liposomes are known in the art. See, for example, Prescott, Ed., Methods in Cell Biology, Volume XIV, Academic Press, New York, N.Y. (1976), p. 33 et seq.
  • Compounds of the present invention that are formed by in vivo conversion of a different compound that was administered to a mammal are intended to be included within the scope of the present invention.
  • Compounds of the present invention may exist as stereoisomers wherein asymmetric or chiral centers are present. These stereoisomers are "R" or "S" depending on the configuration of substituents around the chiral carbon atom. The present invention contemplates various stereoisomers and mixtures thereof. Stereoisomers include enantiomers and diastereomers, and mixtures of enantiomers or diastereomers. Individual stereoisomers of compounds of the present invention may be prepared synthetically from commercially available starting materials which contain asymmetric or chiral centers or by preparation of racemic mixtures followed by resolution well-known to those of ordinary skill in the art. These methods of resolution are exemplified by (1) attachment of a mixture of enantiomers to a chiral auxiliary, separation of the resulting mixture of diastereomers by recrystallization or chromatography and liberation of the optically pure product from the auxiliary or (2) direct separation of the mixture of optical enantiomers on chiral chromatographic columns.
  • The compounds of the invention can exist in unsolvated as well as solvated forms, including hydrated forms, such as hemi-hydrates. In general, the solvated forms, with pharmaceutically acceptable solvents such as water and ethanol among others are equivalent to the unsolvated forms for the purposes of the invention. The compounds of the present invention are suitable for inhibiting the binding of α4β1 integrin to VCAM-1. With respect to the use of the compounds of the present invention as a medicament, the compounds can be used either in vitro or in vivo. In this context, a cell expressing α4β1 integrin is.exposed to a cell expressing VCAM-1 in the presence of an effective inhibiting amount of a compound of the present invention.
  • A cell expressing α4β1 integrin can be a naturally occurring white blood cell, mast cell or other cell type that naturally expresses α4β1 on the cell surface, or a cell transfected with an expression vector that contains a poly-nucleotide (e.g., genomic DNA or cDNA) that encodes α4β1 integrin. In an especially preferred embodiment, α4β1 integrin is present on the surface of a white blood cell such as a monocyte, a lymphocyte or a granulocyte (e.g., an eosinophil or a basophil).
  • A cell that expresses VCAM-1 can be a naturally occurring cell (e.g. an endothelial cell) or a cell transfected with an expression vector containing a polynucleotide that encodes VCAM-1. Methods for producing transfected cells that express VCAM-1 are well known in the art.
  • Where VCAM-1 exists on the surface of cell, the expression of that VCAM-1 is preferably induced by inflammatory cytokines such as tumor necrosis factor-α, interleukin-4 and interleukin-1β.
  • Where the cells expressing α4β1 integrin and VCAM-1 are in a living organism, a compound of the present invention is administered in an effective amount to the living organism. Preferably, the compound is in a pharmaceutical composition of this invention. The compounds and compositions of the present invention are used for manufacturing medicaments for selected from the group consisting of asthma, atherosclerosis, rheumatoid arthritis, allergy, multiple sclerosis, lupus, inflammatory bowel disease, graft rejection, contact hypersensitivity, type I diabetes, leukemia, and brain cancer. Administration is preferably accomplished via intravascular, subcutaneous, intranasal, transdermal or oral delivery.
  • The compounds of the present invention are suitable for selectively inhibiting the binding of α4β1 integrin to a protein comprising exposing the integrin to the protein in the presence of an effective inhibiting amount of a compound of the present invention. In a preferred embodiment, the α4β1 integrin is expressed on the surface of a cell, either naturally occurring or a cell transformed to express α4β1 integrin.
  • The protein to which the α4β1 integrin binds can be expressed either on a cell surface or be part of the extracellular matrix. Especially preferred proteins are fibronectin or invasin.
  • The ability of compounds of the present invention to inhibit binding is described in detail hereinafter in the Examples.
    • Example 1
  • Compound 8, (3S)-3-(1,3-benzodioxol-5-yl)-3-((2R,S)-2-(3-benzyl-5-methyl-2-oxo-1(2H)-pyridinyl)hexanoylamino)propanoic acid, of the structure shown below, was synthesized as follows.
    Figure imgb0018
     The structures of the compounds identified by number in this Example are found in Scheme 1 above.
    • Step 1: A solution of 540 mg of 2-aminohexanoic acid methyl ester hydrochloride salt 1 in 20 ml of methylene chloride was washed with excess saturated sodium bicarbonate. The organic layer was separated, dried over magnesium sulfate, and concentrated in vacuo to give 365 mg of 2-aminohexanoic acid methyl ester as a colorless oil. This material was combined with 5 ml of benzene, 0.28 ml of propionaldehyde, and excess magnesium sulfate. After stirring for 15 minutes, the reaction mixture was filtered and concentrated in vacuo to yield 420 mg of compound 2 as a colorless oil. Compound 2 was used directly without further purification.
    • Step 2: To an ice-bath cooled solution of 1050 mg of compound 2 in 10 ml of diethyl ether, under a positive nitrogen atmosphere, was added 0.80 ml of triethylamine, and a solution of 964 mg of 3-phenylpropanoyl chloride in 2 ml of diethyl ether. The ice bath was removed and the reaction mixture stirred for 30 minutes. The reaction mixture was then concentrated in vacuo and the residual materials further separated by silica gel chromatography using 15% ethyl acetate / hexane as the eluant to yield 468 mg of compound 3 as a colorless oil. Compound 3: 1H NMR (CDCl3): δ 0.87 (t, J = 7.0 Hz, 3H), 1.26 (m, 4H), 1.68 (dd, J = 7.0, 1.1 Hz, 3H), 1.74 (m, 1H), 1.97 (m, 1H), 2.70 (t, J = 7.9 Hz, 2H), 2.96 (t, J = 7.9 Hz, 2H), 3.68 (s, 3H), 4.96 (dd, J. = 10. 1, 5.3 Hz, 1H), 5.32 (dq, J = 13.9, 7.0 Hz, 1H), 6.13 (dd, J = 13.9, 1.1 Hz, 1H), 7.20 (m, 2H), 7.25 (m, 3H).
    • Step 3: N,N-Dimethylformamide (1.63 ml) was added dropwise to an ice-cooled flask containing 4.57 ml of phosphorus oxychloride sealed under a positive nitrogen atmosphere. After 5 minutes, the reaction solution was cannulated into a flask containing 2.22 gm of compound 3. This mixture was stirred at room temperature under a positive nitrogen atmosphere for 2 hours and then heated at 75 °C for 46 hours. The dark-colored reaction mixture was poured over ice and mixed with an excess of sodium bicarbonate and ethyl acetate. The mixture was saturated with sodium chloride and the organic layer separated. The aqueous layer was extracted (3 X 100 ml) with ethyl acetate. The combined organic materials were dried over magnesium sulfate and concentrated in vacuo to yield 1.70 gm of a dark-colored oil. Methylene chloride extraction (3 X) of the aqueous layer yielded an additional 200 mg of material after drying (MgSO4) and condensation in vacuo. The combined residual oils were further purified by silica gel chromatography using 20% -25% ethyl acetate / hexane as the eluant to yield 815 mg of compound 4 as a yellow oil. Compound 4: 1H NMR (CDCl3): δ 0.87 (t, J = 7.2 Hz, 3H), 1.18 (m, 1H), 1.31 (m, 3H), 1.87 (m, 1H), 2.00 (d, J = 0.7 Hz, 3H), 2.16 (m, 1H), 3.72 (s, 3H), 3.85 (br. s, 2H), 5.57 (dd, J = 10.1,5.7 Hz, 1H), 6.82 (br. s, 1H), 6.94 (br. s, 1H), 7.23 (m, 3H), 7.30 (m, 2H).
    • Step 4: To a solution of 86 mg of compound 4 in 3 ml of tetrahydrofuran was added 1 ml of 2N sodium hydroxide and 2 ml of methanol. After complete hydrolysis, the reaction mixture was acidified with 2N hydrochloric acid and saturated with sodium chloride. The mixture was extracted (3X) with ethyl acetate and the combined extracts were dried with magnesium sulfate and concentrated in vacuo to yield 80 mg of compound 5 as a light yellow oil. Compound 5: 1H NMR (CDCl3): δ 0.88 (t, J = 7.1 Hz, 3H), 1.18 (m, 1H), 1.33 (m, 3H), 2.04.(d, J = 0.7 Hz, 3H), 2.07 (m, 1H), 2.27 (m, 1H), 3.86 (d, J = 16.1 Hz, 1H), 3.90 (d, J = 16.1 Hz, 1H), 5.04 (dd, J = 9.0, 6.8 Hz, 1H), 6.96 (br. s, 1H), 6.98 (br. s, 1H), 7.23 (m, 3H), 7.31.(m, 2H).
    • Step 5: To a solution of 80 mg of compound 5 in 1 ml of N,N-dimethylformamide at room temperature and under a positive nitrogen atmosphere, was added 78 mg of (S)-compound 6, 0.057 ml of diisopropylethylamine, and 137 mg ofHBTU. The mixture was stirred for 16 hours and then mixed with 1:1 ethyl acetate / hexane. This mixture was washed with 2N hydrochloric acid, saturated sodium bicarbonate, water (2X), and finally brine. The resulting solution was dried over magnesium sulfate and concentrated in vacuo to yield 156 mg of a yellow oil. This material was further purified by silica gel chromatography using 25% ethyl acetate as the eluant to give 109 mg of compound 7 as a colorless oil. Compound 7: (least polar diastereomer): 1H NMR (CDCl3): δ 0.85 (t, J = 7.1 Hz, 3H), 1.11 (t, J =7.1 Hz, 3H), 1.18 (m, 1H), 1.30 (m, 3H), 1.78 (m, 1H), 2.02 (d, J = 0.8 Hz, 3H), 2.14 (m, 1H), 2.57 (dd, J = 15.4, 7.1 Hz, 1H), 2.66 (dd, J = 15.4, 6.6 Hz, 1H), 3.86 (br. s, 2H), 3.95 (q, J = 7.1 Hz, 2H), 5.17 (m, 1H), 5.42 (t, J = 7.7 Hz, 1H), 5.93 (s, 2H), 6.72 (m, 2H), 6.74 (m, 1H), 6.90 (m, 1H), 7.11 (br. s, 1H), 7.23 (m, 3H), 7.30 (m, 2H), 7.37 (d, J = 7.7 Hz, 1H).
    • Step 6: A solution composed of 109 mg of compound 7, 3 ml of tetrahydrofuran, 1 ml of 2N sodium hydroxide, and 2 ml of methanol was stirred at room temperature until hydrolysis was complete. The mixture was then diluted with water and extracted with diethyl ether. The aqueous layer was acidified with 2N hydrochloric acid and extracted (3X) with ethyl acetate. The combined extracts were dried with magnesium sulfate and concentrated in vacuo to yield 103 mg of compound 8, a 1:1 diasteroisomeric mixture, as an off-white foam.
  • The diastereomeric mixture was separated by reverse-phase HPLC using a 30 -55% acetonitrile / water gradient to yield Compound 9 (R,S) and Compound 10 (S,S).
  • Compound 9 (most polar diastereomer): 1H NMR (CD3SOCD3): δ 0.83 (t, J = 7.1 Hz, 3H), 1.13 (m, 2H), 1.26 (m, 2H), 1.76 (m, 1H), 1.96 (s overlapping m, 4H), 2.62 (dd, J = 15.8, 6.6 Hz, 1H), 2.70 (dd, J =15.8, 8.4 Hz, 1H), 3.69 (d, J = 14.8 Hz, 1H), 3.73 (d. J = 14.8 Hz, 1H), 5.09 (m, 1H), 5.47 (dd, J = 9.2,6.6 Hz, 1H), 6.71 (dd, J = 8.0, 1.5 Hz, 1H), 6.77 (d, J = 8.0 Hz, 1H), 6.84 (d, J = 1.5 Hz, 1H), 7.00 (d, J = 1.8 Hz, 1H), 7.14-7.30 (m, 6H), 8.70 (d, J = 8.1 Hz, 1H).
  • Compound 10: (least polar diastereomer) NMR (CD3SOCD3): δ 0.76 (t, J = 7.3 Hz, 3H), 1.01 (m, 2H), 1.20 (m, 2H), 1.98 (br. s, 3H), 2.60 (dd, J = 15.8, 7.0 Hz, 1H), 2.68 (dd, J =15.8, 7.7 Hz, 1H), 3.71 (d, J = 15.0 Hz, 1H), 3.76 (d, J = 15.0 Hz, 1H), 5.05 (ddd, J = 8.0, 7.7, 7.0 Hz, 1H), 5.51 (dd, J = 9.2, 6.6 Hz, 1H), 5.98 (s, 2H), 6.77 (dd, J = 8.0, 1.4 Hz, 1H), 6.83, (d, J = 8.0 Hz, 1H), 6.89 (d, J = 1.4 Hz, 1H), 7.02 (d, J = 2.2 Hz, 1H), 7.18 (m, 1H), 7.25 (m, 4H), 7.38 (m, 1H), 8.79 (d, J = 8.0 Hz, 1H), 12.08 (br. s, 1H).
    • Example 2
  • Compound 12, (3,S)-3-((2R,S)-2-(3-benzyl-5-methyl-2-oxo-1(2H)-pyridinyl)hexanoylamino)-3-(2,3-dihydro-1-benzofuran-5-yl)propanoic acid, shown below, was synthesized according to the procedure of Example 1, except that compound A, shown below, was substituted for compound 6 in step 5.
    Figure imgb0019
    Figure imgb0020
    • Example 3
  • Compound 13, (3S)-3-((2R,S)-2-(3-benzyl-5-methyl-2-oxo-1(2H)-pyridinyl)hexanoylamino)-3-(4-methylphenyl)propanoic acid, shown below, was obtained by the procedure of Example 1,
    Figure imgb0021
     except that compound B, shown below, was substituted for compound 6 in step 5.
    Figure imgb0022
    • Example 4
  • Compound 14, (3S)-3-((2R,S)-2-(3-benzyl-5-methyl-2-oxo-1(2H)-pyridinyl)hexanoylamino)-3-(4-fluorophenyl)propanoic acid, shown below was obtained by the procedure of Example 1,
    Figure imgb0023
     except that compound 11, shown below, was substituted for compound 6 in step 5.
    Figure imgb0024
    • Example 5
  • Compound 15, (3S)-3-(1,3-benzodioxol-5-yl)-3-((2R,S)-2-(3-(4-methoxybenzyl)-5-methyl-2-oxo-1(2H)-pyridinyl)hexanoylamino)propanoic acid, shown below, can be obtained by the procedure of Example 1,
    Figure imgb0025
     except that 3-(4-methoxyphenyl)-propanoyl chloride should be substituted for 3-phenylpropanoyl chloride in step 2.
    • Example 6
  • Compound 16, (3S)-3-(1,3-benzodioxol-5-yl)-3-((2R,S)-2-(3-(4-methylbenzyl)-5-methyl-2-oxo-1(2H)-pyridinyl)hexanoylamino)propanoic acid, shown below can be obtained by the procedure of Example 1,
    Figure imgb0026
     except that 3-(4-methylphenyl)-propanoyl chloride should be substituted for 3-phenylpropanoyl chloride in step 2.
    • Example 7
  • Compound 17, (3S)-3-(1,3-benzodioxol-5-yl)-3-((2R,S)-2-(3-(4-fluorobenzyl)-5-methyl-2-oxo-1(2H)-pyridinyl)hexanoylamino)propanoic acid, shown below, was obtained by the procedure of Example 1,
    Figure imgb0027
     except that 3-(4-fluorophenyl)-propanoyl chloride was substituted for 3-phenylpropanoyl chloride in step 2.
    • Example 8
  • Compound 18, (3S)-3-(1,3-benzodioxol-5-yl)-3-((2R,S)-2-(3-(4-chlorobenzyl)-5-methyl-2-oxo-1(2H)-pyridinyl)hexanoylamino)propanoic acid, shown below was obtained by the procedure of Example 1,
    Figure imgb0028
     except that 3-(4-chlorophenyl)-propanoyl chloride was substituted for 3-phenylpropanoyl chloride in step 2.
    • Example 9
  • Compound 19, (3S)-3-(1,3-benzodioxol-5-yl)-3-((2R,S)-2-(3-(4-chlorobenzyl)-5-methyl-2-oxo-1(2H)-pyridinyl)hexanoylamino)propanoic acid, shown below was obtained by the procedure of Example 1,
    Figure imgb0029
     except that 3-(3-chlorophenyl)-propanoyl chloride was substituted for 3-phenylpropanoyl chloride in step 2.
    • Example 10 Synthesis of (3S)-3-(1,3-benzodioxol-5-yl)-3-({(2S)-2-[2-oxo-3-(2-thienylmethyl)-1-imidazolidinyl]hexanoyl}amino)propanoic acid (20).
    • Step One: To a solution of 6 (680 mg, 2.87 mmol) and N-tert-butoxycarbonyl-L-norleucine (696 mg, 3.01 mmol) in DMF (14.4 ml) at room temperature under a dry nitrogen atmosphere, N, N-diisopropylethylamine (0.52 ml, 3.0 mmol) and HBTU (1.25 g, 3.3 mmol) were added sequentially. The resulting mixture was stirred at room temperature overnight then was diluted with a 1:1 mixture of hexanes:ethyl acetate and washed 2N HCl, H2O, saturated NaHCO3, H2O (3X) and brine. The organic phase was dried over MgSO4 and filtered and the filtrate was concentrated under reduced pressure to give 22 (1.27g, 98%) as a light yellow solid.
    • Step Two: To a flask containing 22 (1.27g, 2.82 mmol) sealed with a rubber septum at room temperature under a dry nitrogen atmosphere, HCl (7.2 ml, 4.0M in dioxane, 28.8 mmol) was added by syringe. The nitrogen needle was removed and the mixture in the sealed flask was stirred for 1 hour. The mixture was diluted with CH2Cl2 and washed with saturated NaHCO3. The organic phase was dried over MgSO4 and filtered and the filtrate was concentrated under reduced pressure to give 23 (892 mg, 90%) as a light yellow oil.
    • Step Three: To a solution of ethanolamine (1.70 g, 27.8 mmol) and 2-thiophenecarboxaldehyde (0.52 ml, 5.6 mmol) in 1,2-dichloroethane (22 ml) at room temperature under a dry nitrogen atmosphere, sodium triacetoxyborohydride (1.66 g, 7.8 mmol) was added. The resulting mixture was stirred at room temperature overnight then was diluted with CH2Cl2 and washed with a 1:1 mixture of saturated NaHCO3 and brine. The aqueous phase was extracted with CH2Cl2 and the organic phases were combined, dried over MgSO4 and filtered. The filtrate was concentrated under reduced pressure to give 24 (840 mg, 97%) as a pale yellow oil.
    • Step Four: A solution of aminal 24 (840 mg, 5.41 mmol) in methanol (10 ml) was stirred at room temperature for 30 minutes, cooled to 0 °C and then sodium borohydride (106 mg, 2.8 mmol) was added. The mixture was allowed to warm to room temperature and was then stirred for 1 hour. The mixture was quenched by dropwise addition of water then diluted with CH2Cl2 and a 1:1 mixture of saturated NaHCO3 and brine. The aqueous phase was extracted with CH2Cl2 (2X) and the organic phases were combined, dried over MgSO4 and filtered. The filtrate was concentrated under reduced pressure to give 25 (420 mg, 49%) as a pale yellow viscous oil.
    • Step Five: A solution of 25 (420 mg, 2.67 mmol) and di-tert-butyl dicarbonate (650 mg, 2.98 mmol) in CH2Cl2 (10 ml) was stirred at room temperature under a dry nitrogen atmosphere for 20 minutes and then concentrated. The residue was filtered though silica gel, eluting with 7:3 hexanes:ethyl acetate increasing to 3:2 hexanes:ethyl acetate to yield 26 (610 mg, 88%) as a colorless, viscous oil.
    • Step Six: To a solution of methylsulfoxide (0.49 ml, 6.9 mmol) in CH2Cl2 (11 ml) cooled to -78 °C under a dry nitrogen atmosphere, oxalyl chloride (1.7 ml, 2.0 M in CH2Cl2, 3.4 mmol) was added by syringe. The resulting mixture was stirred at -78°C for 15 minutes, then a solution of 26 (590 mg, 2.3 mmol) in CH2Cl2 (10 ml) was added by cannula along with a CH2Cl2 (5 ml) rinse. The mixture was stirred at -78 °C for 30 minutes, triethylamine (0.96 ml, 6.9 mmol) was added and the mixture was allowed to warm to room temperature. The mixture was diluted with CH2Cl2 and washed with saturated NaHCO. The organic phase was dried over MgSO4 and filtered and the filtrate was concentrated under reduced pressure to give 27 (630 mg) as a light yellow oil. This material was used without purification.
    • Step Seven: To a solution of 27 (102 mg, 0.40 mmol) and 23 (140 mg, 0.40 mmol) in 1,2-dichloroethane (4 ml) at room temperature under a dry nitrogen atmosphere, sodium triacetoxyborohydride (119 mg, 0.56 mmol) was added. The resulting mixture was stirred for 2 hours, then was diluted with ethyl acetate and washed with saturated NaHCO3 and brine. The organic phase was dried over MgSO4 and filtered and the filtrate was concentrated under reduced pressure to give 28 (232 mg) as a light yellow oil. This material was used without purification.
    • Step Eight: To a flask containing 28 (232 mg crude material, 0.40 mmol theoretical from previous step) sealed with a rubber septum at room temperature under a dry nitrogen atmosphere, HCl (1.95 ml, 4.0M in dioxane, 7.8 mmol) was added by syringe. The nitrogen needle was removed and the mixture in the sealed flask was stirred for 15 minutes. The mixture was diluted with CH2Cl2 and washed with a 1:1 mixture of saturated NaHCO3:brine. The organic phase was dried over MgSO4 and filtered and the filtrate was concentrated under reduced pressure to give 29 (180 mg) as a light yellow oil. This material was used without purification.
    • Step Nine: To a solution of 29 (180 mg crude material, 0.40 mmol theoretical from previous step) in 1,2-dichloroethane (3.7 ml) at room temperature under a dry nitrogen atmosphere, carbonyldiimidazole (66 mg, 0.41 mmol) was added. The mixture was heated to 50 °C (oil bath temperature) for 1 hour, the was concentrated. The residue was taken up in ethyl acetate and washed with 2N HCl, H2O, saturated NaHCO3 and brine. The organic phase was dried over MgSO4 and filtered and the filtrate was concentrated under reduced pressure. The residue was filtered through silica gel, eluting with 3:2 hexanes:ethyl acetate increasing to 1:1 hexanes: ethyl acetate to yield 30 (114 mg, 55% for 3 steps) as a colorless oil.
    • Step Ten: To a solution of 30 (114 mg, 0.22 mmol) in THF (3 ml) at room temperature, NaOH (1 ml, 2N in H2O, 2 mmol) and methanol (enough to give a clear solution, approximately 2 ml) were added. The resulting mixture was stirred for 15 minutes, then was diluted with water and extracted with ether. The aqueous phase was acidified with HCl (2N) and extracted with ethyl acetate. The ethyl acetate layer was washed with brine, dried over MgSO4 and filtered and the filtrate was concentrated under reduced pressure to give 20 (111 mg, 100%) as a white foam. 1H NMR (400 MHz, CD3SOCD3) δ 0.82 (t, J = 7.3 Hz, 3H), 1.09 (m, 2H), 1.25 (m, 2H), 1.48 (m, 1H), 1.64 m, 1H), 2.61 (dd, J = 15.8, 7.0 Hz, 1H), 2.70 (dd, J = 15.8, 8.0 Hz, 1H), 3.20 (m, 3H), 3.50 (m, 1H), 4.27 (dd, J = 9.5, 5.9 Hz, 1H), 4.38 (d, J = 15.6 Hz, 1H), 4.54 (d, J = 15.6 Hz, 1H), 5.08 (ddd, J = 8.1, 8.0, 7.0 Hz, 1H), 5.91 (s, 2H), 6.76 (dd, J = 8.0, 1.5 Hz, 1H), 6.83 (d, J = 8.0 Hz, 1H), 6.88 (d, J = 1.5 Hz, 1H), 6.99 (m, 2H), 7.43 (dd, J = 4.4, 1.8 Hz, 1H), 8.43 (d, J = 8.1 Hz, 1H).
  • Synthetic procedures similar to those described above may be utilized to obtain the following compounds: (3S)-(1,3-benzodioxol-5-yl)-3-(((2S)-2-(2-oxo-3-(2-thienylmethyl)tetrahydro-1(2H)-pyrimidinyl)hexanoyl)amino) propanoic acid, (3S)-3-(1,3-benzodioxol-5-yl)-3-(((2S)-2-(2-oxo-4-(2-thienyl)-3-(2-thienylmethyl)tetrahydro-1((2H)-pyrimidinyl)hexanoyl)amino)propanoic acid and (3S)-3-(1,3-benzodioxol-5-yl)-3-(((2S)-2-(2-oxo-3-(2-thienylmethyl)-1,3-diazepan-1-yl)hexanoyl)amino)propanoic acid.
    • Example 11 Synthesis of (3S)-3-(1,3-benzodioxol-5-yl)-3-({(2S)-2-[2-oxo-3-(phenylcarbonyl)-1(2H)-pyridinyl]hexanoyl}amino)propanoic acid (31).
  • Figure imgb0030
    • Step One: A solution of 23 (541 mg, 1.54 mmol) and ethyl benzoylacetate (0.53 mL, 3.09 mmol) in toluene (15 mL) was heated to reflux for 2 hours. The resulting mixture was cooled to room temperature and concentrated under reduced pressure. The residue was recrystallized from hexanes/CH2Cl2 to give compound 32 (310 mg, 40%) as a pale yellow solid.
    • Step Two: To a suspension of 32 (851 mg, 1.71 mmol) in ethanol (absolute, 6.8 mL) and acetic acid (glacial, 0.34 mL) at room temperature under nitrogen, 3-(dimethylamino)acrolein (1.02 mL, 10.2 mmol) was added by syringe. The resulting mixture was heated to reflux overnight, cooled to room temperature and diluted with ethyl acetate. This mixture was washed with HCl (2N, twice) and brine. The organic phase was dried over MgSO4 and filtered and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel chromatography, eluting with 3:2 hexanes:ethyl acetate to give 33 (476 mg, 52%) as a light yellow oil.
    • Step Three: To a solution of 33 (115 mg, 0.22 mmol) in THF (6 mL) at room temperature, aqueous NaOH (2N, 2 mL) and methanol (4 mL) were added. The resulting solution was stirred for 15 minutes, diluted with water and extracted with Et2O. The aqueous phase was acidified with HCl (2N) and was extracted with ethyl acetate. The ethyl acetate layer was washed with water and brine, dried over MgSO4 and filtered. The filtrate was concentrated under reduced pressure to give (3S)-3-(1,3-benzodioxol-5-yl)-3-({(2S)-2-[2-oxo-3-(phenylcarbonyl)-1(2H)-pyridinyl]hexanoyl}amino)propanoic acid (31, 100 mg, 92%) as a pale yellow foam. 1H NMR (400 MHz, CD3SO2CD3): δ 0.81 (t, J = 7.3 Hz, 3H), 1.08 (m, 2H), 1.25 (m, 2H), 1.80 (m, 1H), 1.93 (m, 1H), 2.61 (dd, J = 15.8,6.8 Hz, 1H), 2.68 (dd, J = 15.8, 7.9 Hz, 1H), 5.09 (m, 1H), 5.49 (dd, J = 9.5, 6.2 Hz, 1H), 5.98 (s, 2H), 6.24 (t, J = 7.0 Hz, 1H), 6.78 (dd, J = 8.1, 1.4 Hz, 1H), 6.84 (d, J = 8.1 Hz, 1H), 6.89 (d, J = 1.4 Hz, 1H), 7.49 (t, J = 7.7 Hz, 2H), 7.62 (m, 1H), 7.70 (m, 3H), 7.97 (dd, J = 7.0, 2.2 Hz, 1H), 8.87 (d, J = 8.1 Hz, 1H), 12.11 (br. s, 1H).
    Example 12 Synthesis of (3S)-3-(1,3-benzodioxol-5-yl)-3-({(2S)-2-[2-oxo-3-(phenylmethyl)-1(2H)-pyridinyl]hexanoyl}amino)propanoic acid (34).
  • Figure imgb0031
    • Step One: To a solution of 33 (88 mg, 0.17 mmol) in ethanol (absolute, 4 mL) at room temperature, NaBH4 (12.5 mg, 0.33 mmol) was added. The resulting mixture was stirred for 20 minutes, then was quenched with HCl (2N, 2 mL). The resulting mixture was diluted with water and ethyl acetate and the organic layer was washed with saturated aqueous NaHCO3 and brine. The organic layer was dried over MgSO4 and filtered and the filtrate was concentrated under reduced pressure to give 35 (85 mg, 96%) as a pale yellow oil. This material was used without purification.
    • Step Two: To a solution of 35 (85 mg, 0.16 mmol) in ethyl acetate (4 mL) at room temperature under nitrogen, Pd/C (10% dry weight basis, Degussa type E101 NE/W, ~50% water content, 36 mmol) was added. The atmosphere was replaced with hydrogen (toggle between vacuum and hydrogen from a balloon five times) and the mixture was vigorously stirred for 1.5 hours. The mixture was filtered through Celite and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel chromatography, eluting with 7:3 hexanes:ethyl acetate to give 36 (32 mg, 39%) as a colorless oil.
    • Step Three: To a solution of 36 (32 mg, 0.062 mmol) in THF (3 mL) at room temperature, aqueous NaOH (2N, 1 mL) and methanol (2 mL) were added. The resulting solution was stirred for 15 minutes, diluted with water and extracted with Et2O. The aqueous phase was acidified with HCl (2N) and was extracted with ethyl acetate. The ethyl acetate layer was washed with water and brine, dried over MgSO4 and filtered. The filtrate was concentrated under reduced pressure. The residue was taken up in acetonitrile (3 mL) and water (7 mL) and the mixture was lyophilized to give (3S)-3-(1,3-benzodioxol-5-yl)-3-({(2S)-2-[2-oxo-3-(phenylmethyl)-1(2H)-pyridinyl]hexanoyl} amino)propanoic acid (34, 31 mg, 100%) as a white powder. 1H NMR (400 MHz, CD3SO2CD3): δ 0.76 (t, J = 7.3 Hz, 3H), 1.01 (m, 2H), 1.22 (m, 2H), 1.70 (m, 1H), 1.87 (m, 1H), 2.60 (dd, J = 15.8, 7.0 Hz, 1H), 2.68 (dd, J = 15.8, 7.9 Hz, 1H), 3.72 (d, J = 15.0 Hz, 1H), 3.77 (d, J = 15.0 Hz, 1H), 5.06 (m, 1H), 5.54 (dd, J = 9.2, 6.6 Hz, 1H), 5.98 (s, 2H), 6.16 (t, J = 7.0 Hz, 1H), 6.77 (dd, J = 8.1, 1.4 Hz, 1H), 6.83 (d, J = 8.1 Hz, 1H), 6.89 (d, J = 1.4 Hz, 1H), 7.13 (m, 1H), 7.18 (m, 1H), 7.26 (m, 4H), 7.59 (dd, J = 7.0, 1.8 Hz, 1H), 8.83 (d, J = 8.1 Hz, 1H), 12.11 (br. s, 1H).
    Example 13 Synthesis of (3S)-3-(1,3-benzodioxol-5-yl)-3-[({1-[2-oxo-3-(phenylmethyl)-1(2H)-pyridinyl]cyclohexyl}carbonyl)amino]propanoic acid.
    • Step One: To a solution of 3-benzylpyridine (1.65 g, 9.77 mmol) in acetone (3.5 mL), 1-chloro-2,4-dinitrobenzene (2.00g, 9.56 mmol) was added and the mixture was refluxed overnight. The mixture was cooled to room temperature, diluted with acetone and the solvent was decanted from the precipitate. The crude solid was washed with acetone (2 times) and diethyl ether (1 time), decanting each time to give 37 (3.57 g, 100%) as a gray solid.
    • Step Two: To a solution of 1-amino-1-hydroxymethylcyclohexane (0.45g, 3.5 mmol) in n-butanol (8.75 mL), solid N-(2,4-dintrophenyl)-3-benzylpyridinum chloride (37, 1.23 g, 3.3 mmol) was added. The resulting solution was heated to reflux for 2.5 days under a nitrogen atmosphere. The mixture was cooled, diluted with water and filtered. The filtrate was basified with concentrated NH4OH (2mL) and extracted with ethyl acetate. The aqueous layer was concentrated to dryness to give 38 (0.56 g) as a yellow oil which was used without further purification.
    • Step Three: To a solution of crude 38 (0.56g, 3.5 mmol theoretical) in water (10 mL), a solution of potassium ferricyanide (3.3 g, 10 mmol) in water (15 mL) was added dropwise via an addition funnel over 30 minutes at 0 °C. A solution of KOH (0.76 g, 13.5 mmol) in water (5 mL) was then added over 30 minutes. Toluene (10 mL) was added and the solution was stirred for one hour at 0 °C. The layers were separated, and the aqueous layer was extracted again with toluene. The combined extracts were dried over Na2SO4 and filtered and the filtrate was concentrated under reduced pressure. The residue was chromatographed on silica gel, eluting with 7:13 hexanes:ethyl acetate to give 39 (20 mg, 1.9%, two steps.)
    • Step Four: To a suspension of 39 (20 mg, 0.068 mmol) in aqueous KOH (1M, 0.70 mL) potassium persulfate (0.073 g, 0.270 mmol) and ruthenium (III) chloride (1mg, catalytic) and THF (0.25 mL) were added. The mixture was stirred for 1 hour and extracted with dichloromethane. The aqueous layer was acidified and extracted with ethyl acetate (3 times). The ethyl acetate extracts were combined, dried over MgSO4 and filtered. The filtrate was concentrated under reduced pressure to give 40 (0.0148 g, 70%) as a tan solid.
      (3S)-3-(1,3-Benzodioxol-5-yl)-3-[({1-[2-oxo-3-(phenylmethyl)-1(2H)-pyridinyl]cyclohexyl}carbonyl)amino]propanoic acid was prepared from 40 according to the procedures described in Example 1. 1H NMR (400 MHz, CD3SO2CD3): δ 1.40 (m, 4H), 1.68 (m, 2H), 2.04 (m, 2H), 2.60 (d, J = 7.0 Hz, 2H), 3.67 (d, J = 15.2 Hz, 1H), 3.72 (d, J = 15.2 Hz, 1H), 5.12 (m, 1H), 5.95 (m, 2H), 6.19 (t, J = 7.0 Hz, 1H), 6.74 (dd, J = 7.8, 1.4 Hz, 1H), 6.76 (d, J = 7.8 Hz, 1H), 6.90 (d, J = 1.4 Hz, 1H), 7.10 (d, J = 5.8 Hz, 1H), 7.20 (m, 5H), 7.57 (d, J = 8.4 Hz, 1H), 7.66 (dd, J = 7.7, 1.8 Hz, 1H).
    Example 14 Synthesis of (3S)-3-(1,3-benzodioxol-5-yl)-3-({2-[2-oxo-5-(phenylmethyl)-1(2H)-pyridinyl]hexanoyl}amino)propanoic acid.
    • Step One: To a mixture of 41 (prepared according to procedures described in Example 13, 1.75 g crude orange oil, 5.0 mmol theoretical) in water (25 mL) at 0 °C, a solution of potassium ferricyanide (4.7 g, 14 mmol) in water (22 mL) was added dropwise via an addition funnel over 30 minutes. A solution of KOH (1.1 g, 19 mmol) in water (7 mL) was then added over 30 minutes. Toluene (15 mL) was added and the solution was stirred for one hour at 0 °C. The layers were separated, and the aqueous layer was extracted again with toluene. The combined extracts were dried over Na2SO4 and filtered and the filtrate was concentrated under reduced pressure. The residue was chromatographed on silica gel, eluting with 7:13 hexanes:ethyl acetate to give 42 (major product, 0.36 g, 29%) and 43 (minor product, 0.10 g, 7.0%).
      (3S)-3-(1,3-Benzodioxol-5-yl)-3-({2-[2-oxo-5-(phenylmethyl)-1(2H)-pyridinyl]hexanoyl}amino)propanoic acid was prepared from 42 according to procedures described in Examples 1 and 13. 1H NMR (400 MHz, CD3SO2CD3) δ: 0.77 (t, J = 7.3 Hz, 3H), 1.00 (m, 2H), 1.20 (m, 2H), 1.75 (m, 1H), 1.88 (m, 1H), 2.65 (m, 2H), 3.70 (s, 2H), 5.08 (m, 1H), 5.49 (dd, J = 9.9, 6.2 Hz, 1H), 5.98 (s, 2H), 6.32 (d, J = 9.2 Hz, 1H), 6.77 (dd, J = 8.1, 1.5 Hz, 1H), 6.83 (d, J = 9.2 Hz, 1H), 6.89 (d, J = 1.5 Hz, 1H), 7.20 (m, 4H), 7.28 (m, 4H), 7.61 (d, J = 2.6 Hz, 1H), 8.81 (d, J = 8.1 Hz, 1H), 12.10 (br. s, 1H).
    Example 15 Synthesis of (3S)-3-(1,3-benzodioxol-5-yl)-3-({(2S)-2-[(3S)-2,5-dioxo-3-(phenylmethyl)-4-(2-thiophenylmethyl)tetrahydro-1 (2H)-pyrazinyl]hexanoyl}amino)propanoic acid.
    • Step 1: To a solution of phenylalanine methyl ester (2.32 g, 12.9 mmol) in DCE (50 ml) at room temperature, 2-thiophenecarboxaldehyde (1.2 ml, 12.9 mmol) and NaBH(OAc)3 (4.11 g, 19.4 mmol) were added. The reaction stirred at room temperature for 24 hours, diluted with CH2Cl2 (300 ml) and washed with water (300 ml). The organic layer was dried over MgSO4 and filtered and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel chromatography, eluting with 9:1 hexanes:ethyl acetate to yield 44 (2.78 g, 78%).
    • Step 2: To a solution of 44 (1.50 g, 5.45 mmol) in methanol (10 ml), tetrahydrofuran (10 ml) and water (10 ml), sodium hydroxide (880 mg, 21.8 mmol) was added. The reaction was stirred at room temperature for 48 hours. The mixture was concentrated under reduced pressure to an aqueous solution and then lyophilized to yield 45 (1.42 g).
    • Step 3: To a solution of 45 (500 mg, 1.91 mmol) and norleucine methyl ester hydrochloride (382 mg, 2.10 mmol) in DMF (10 ml) at room temperature, 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (401 mg, 2.10 mmol), 1- hydroxybenzotriazole (238 mg, 2.10 mmol) and 4-methylmorpholine (0.23 ml, 2.10 mmol) were added. The reaction stirred at room temperature for 24 hours then the mixture was taken up in ethyl acetate (200 ml) and washed with water (2 times, 200 ml). The organic layer was dried over MgSO4 and filtered and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel chromatography, eluting with 9:1 hexanes:ethyl acetate to yield 46 (422 mg, 57%).
    • Step 4: To a solution of 46 (415 mg, 1.07 mmol) DCE (10 ml) and triethylamine (0.15 ml, 1.07 mmol) at 0 °C, bromoacetyl bromide (0.090 ml, 1.07 mmol) was added and the reaction was warmed to room temperature and stirred for 24 hours. The mixture was taken up in CH2Cl2 (150 ml) and washed with water (150 ml). The organic layer was dried over MgSO4 and filtered and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel chromatography, eluting with 4:1 hexanes:ethyl acetate to yield 47 (381 mg, 70%).
    • Step 5: To a solution of 47 (375 mg, 0.74 mmol) in THF (8 ml), Cs2CO3 (360 mg, 1.10 mmol) was added. The reaction was stirred at room temperature for 4 hours. The mixture was taken up in ethyl acetate (150 ml) and washed with water (150 ml) The organic layer was dried over MgSO4 and filtered and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel chromatography, eluting with 4:1 hexanes:ethyl acetate to yield 48 (145.0 mg, 46%).
  • (3S)-3-(1,3-benzodioxol-5-yl)-3-({(2S)-2-[(3S)-2,5-dioxo-3-(phenylmethyl)-4-(2-thiophenylmethyl)tetrahydro-1 (2H)-pyrazinyl]hexanoyl}amino)propanoic acid was prepared from 48 according to procedures described in Example 1. MS: Calculated: (M - H) = 604.2 m/z; Found: (M - H) = 604.4 m/z.
    • Example 16 Synthesis of (3S)-3-(1,3-benzodioxol-5-yl)-3-({2-[2-oxo-3-(phenylmethyl)-2,3-dihydro-1 H-benzimidazol-1-yl]acetyl} amino)propanoic acid.
    • Step One: A mixture of 1-fluoro 2-nitrobenzene (0.50 g, 3.54 mmol), benzylamine (0.38 g, 3.54 mmol) and K2CO3 (0.98 g, 7.08 mmol) in DMF (10 mL) was stirred at room temperature overnight. The mixture was then partitioned between EtOAc and water. The organic layer was washed with water and brine, dried over MgSO4 and filtered. The filtrate was concentrated to dryness to give 49 (0.79 g, 98%) as an orange solid.
    • Step Two: To a solution of 49 (0.79 g, 3.5 mmol) in ethanol (7.0 mL) and acetic acid (7.0 mL) at room temperature, Fe powder (2.44 g, 34.6 mmol) was added and the suspension was stirred vigorously at 40 °C until thin layer chromatography indicated complete consumption of 49. The mixture was filtered through Celite, washing with chloroform. The filtrate was diluted with saturated sodium bicarbonate and the chloroform layer was dried over Na2SO4 and filtered. The filtrate was concentrated under reduced pressure and the residue was purified by chromatography on silica gel (4:1 increasing to 1:1 hexanes:ethyl acetate) to give compound 50 (0.35 g, 50%)
    • Step Three: A solution of 50 (0.25 g, 1.26 mmol) and CDl (0.22 g, 1.4 mmol) in CH2Cl2 (12 mL) was stirred at room temperature overnight. The mixture was diluted with EtOAc and was washed with 1N HCl (3x) and brine. The organic layer was dried over MgSO4 and filtered and the filtrate was concentrated under reduced pressure to give 51 (0.23 g, 82%) as a brown solid.
    • Step Four: To a solution of 51 (0.19 g, 0.85 mmol) in anhydrous DMF (5 mL) at 0 °C was added NaH (60 % dispersion in mineral oil, 0.044 g, 1.1 mmol). The mixture was stirred at 0 °C for 10 minutes before the addition of ethyl bromoacetate (0.21 g, 0.13 mmol). After stirring at room temperature overnight, the mixture was poured into ice-water and extracted with EtOAc (2 times). The organic layer was washed with water and brine, dried over MgSO4 and filtered. The filtrate was concentrated under reduced pressure to give 52 (0.25 g, 95 %) as a brown solid.
  • (3S)-3-(1,3-benzodioxol-5-yl)-3-({2-[2-oxo-3-(phenylmethyl)-2,3-dihydro-1H-benzimidazol-1-yl]acetyl}amino)propanoic acid was prepared from 52 according to procedures described in Example 1. 1H NMR (400 MHz, CD3COCD3): δ 2.79 (m, 2H), 4.56 (m, 2H), 5.02 (s, 2H), 5.31 (m, 1H), 5.90 (s, 2H), 6.92 (m, 7H), 7.25 (m, 5H), 7.91 (d, J = 8.4 Hz, 1H), 10.79 (br. S, 1H).
    • Example 17 Synthesis of (3S)-3-(1,3-benzodioxol-5-yl)-3-({2-[5,5-dimethyl-2,4-dioxo-3-(phenylmethyl)tetrahydro-1H-imidazol-1-yl]hexanoyl} amino) propanoic acid.
    • Step One: To a solution of 5,5-dimethylhydantoin (2.00 g, 15.6 mmol) in DMF (30 mL) at room temperature, K2CO3 (6.5 g, 47 mmol) and benzyl chloride (2.20 mL, 18.7 mmol) were added. The resulting mixture was stirred overnight, diluted with water and extracted with ethyl acetate. The organic layer was washed with brine, dried over MgSO4 and filtered. The filtrate was concentrated under reduced pressure and the residue was purified by silica gel chromatography, eluting with 6:1 increasing to 3:1 hexanes:ethyl acetate to yield 53 (3.21 g, 94%).
  • (3S)-3-(1,3-benzodioxol-5-yl)-3-({2-[5,5-dimethyl-2,4-dioxo-3-(phenylmethyl)tetrahydro-1H-imidazol-1-yl]hexanoyl}amino)propanoic acid was prepared from 53 according to procedures described in Examples 1 and 16. MP: 53-55 °C.
    • Example 18 Synthesis of (3S)-3-(1,3-benzodioxol-5-yl)-3-({(2S)-2-[2,4-dioxo-1-(phenylmethyl)-1,4-dihydro-3(2H)-quinazolinyl]hexanoyl}amino)propanoic acid.
    • Step One: To a solution of anthranillic acid (450 mg, 3.30 mmol) and norleucine methyl ester hydrochloride (500 mg, 2.75 mmol) in dimethylformamide (10 ml) at room temperature, 1-[3-(dimethylamino) propyl]-3-ethylcarbodiimide hydrochloride (640 mg, 3.30 mmol), 1-hydroxybenzo triazole (450 mg, 3.30 mmol), and 4-methylmorpholine (610 mg, 5.50 mmol) were added. The reaction was stirred at room temperature for 24 hours then the mixture was taken up in ethyl acetate (200 ml) and washed with water (2 x 200 ml). The organic layer was dried over MgSO4 and filtered and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel chromatography, eluting with 4:1 increasing to 1:1 hexanes:ethyl acetate to yield 54 (860 mg, 99%).
    • Step Two: A solution of 54 (0.86 g, 3.26 mmol) and CDI (0.79 g, 4.89 mmol) in anhydrous C1CH2CH2Cl (30 mL) was heated at 85 °C overnight. The mixture was cooled to room temperature and concentrated and the residue was brought up in EtOAc. The organic layer was washed with 1N HCl (3 x) and brine, dried over MgSO4 and filtered. The filtrate was then concentrated under reduced pressure and the residue was purified by silica gel chromatography ( hexanes:EtOAc, 5:1 increasing to 1:1) to give 55 as a white solid (0.67 g, 71%). (3S)-3-(1,3-benzodioxol-5-yl)-3-({(2S)-2-[2,4-dioxo-1-(phenylmethyl)-1,4-dihydro-3(2H)-quinazolinyl]hexanoyl}amino)propanoic acid was prepared from 55 according to procedures outlined in Examples 1 and 16. 1H NMR (400 MHz, CD3SO2CD3): δ 0.80 (m, 3H), 1.1-1.6 (m, 4H), 2.03 (m, 1H), 2.20 (m, 1H), 2.63 (m, 2H), 5.20 (m, 2H), 5.35 (m, 1H), 5.47 (m, 1H), 5.91 (d, J = 11.0 Hz, 1H), 5.96 (d, J = 3.3 Hz, 1H), 6.64-6.87 (m, 3H), 7.30 (m, 6H), 7.68 (m, 1H), 8.14 (m, 2H), 12.09 (br. S, 1H).
    Example 19 Synthesis of (3S)-3-(1,3-benzodioxol-5-yl)-3-({2-[3-methyl-6-oxo-5-(phenylmethyl)-1(6H)-pyridazinyl]hexanoyl}amino)propanoic acid.
    • Step One: To a mixture of dihydropyridazinone (2.50 g, 19.21 mmol) in EtOH (6 mL) at room temperature, benzaldehyde (2.04 g, 19.21 mmol) and solid KOH (1.3 g, 23.05 mmol) were added. This mixture was heated to 85 °C overnight, cooled to room temperature and poured into ice water. The resulting mixture was acidified to pH = 4 with concentrated HCl and the precipitate was collected by filtration, washing with water. The resulting solid was then dried in vacuo to give 56 (3.6 g, 85 %).
  • (3S)-3-(1,3-benzodioxol-5-yl)-3-({2-[3-methyl-6-oxo-5-(phenylmethyl)-1(6H)-pyridazinyl]hexanoyl}amino)propanoic acid was prepared from 56 according to procedures described in Examples 1 and 16. 1H NMR (400 MHz, CD3SO2CD3): δ 0.80 (m, 3H), 1.18 (m, 4H), 1.95 (m, 2H), 2.18 (s, 3H), 2.65 (m, 2H), 3.79 (m, 2H), 5.06 (m, 1H), 5.26 (m, 1H), 5.97 (d, J = 2.2 Hz, 2H), 6.81 (m, 3H), 6.98 (s, 1H), 7.27 (m, 5H), 8,27 (m, 1H), 12.14 (br. S, 1H).
    • Example 20 Synthesis of (3S)-3-(1,3-benzodioxol-5-yl)-3-({2-[2-oxo-3-(phenylmethyl)-3,4-dihydro-1(2H)-quinazolinyl]hexanoyl}amino)propanoic acid.
    • Step 1: A solution of 2-nitrobenzylbromide (0.50 g, 2.31 mmol) and benzylamine (0.49 g, 4.62 mmol) in THF (5 mL) was stirred at room temperature overnight and was then diluted with EtOAc. The organic layer was washed with 1 N NaOH (twice) and brine, dried over MgSO4 and filtered. The filtrate was concentrated under reduced pressure and the residue was purified by silica gel chromatography (hexanes:EtOAc, 3:1 increasing to 1:1) to give 57 (0.5 g, 89 %) as an oil.
  • (3S)-3-(1,3-benzodioxol-5-yl)-3-({2-[2-oxo-3-(phenylmethyl)-3,4-dihydro-1(2H)-quinazolinyl]hexanoyl}amino)propanoic acid was prepared with 57 according to procedures described in Examples 1 and 16. 1H NMR (400 MHz, CD3SO2CD3): δ 0.78 (m, 3H), 1.21 (m, 4H), 1.88 (m, 1H), 2.14 (m, 1H), 2.65 (m, 2H), 4.26 (m, 2H), 4.43 (m, 1H), 4.80 (m, 1H), 5.03 (m, 1H), 5.18 (m, 1H), 5.92 (d, J = 4.0 Hz, 1H), 5.97 (s, 1H), 6.70 (m, 2H), 6.80 (m, 1H), 6.95 (m, 2H), 7.12 (m, 2H), 7.30 (m, 5H), 8.20 (m, 1H), 12.09 (br. s, 1H).
    • Example 21 Synthesis of (3S)-3-(1,3-benzodioxol-5-yl)-3-({2-[2-oxo-3-(phenylmethyl)-1(2H)-quinoxalinyl]hexanoyl} amino)propanoic acid.
    • Step One: To solution of 1,2-phenylenediamine (2.64 g, 14.4 mmol) and phenylpyruvic acid (2.00 g, 12.2 mmol) in ethanol (absolute, 20 mL), a solution of 2-mercaptoethanol (1.6 mL) in 2N HCl (18.3 mL) was added. The resulting mixture was heated to reflux for 2 hours, then was allowed to cool to room temperature and filtered, washing the precipitate with ethanol (twice). The precipitate was dried under vacuum to give 58 (1.88 g, 65%) as a white solid.
  • (3S)-3-(1,3-Benzodioxol-5-yl)-3-({2-[2-oxo-3-(phenylmethyl)-1(2H)-quinoxalinyl]hexanoyl}amino)propanoic acid was prepared from 58 according to procedures described in Examples 1 and 16. MS: Calculated (M - H)- = 540.21; Found (M - H)- = 540.21.
    • Example 22 Synthesis of (3S)-3-(1,3-benzodioxol-5-yl-3-((2S)-2-(3-benzyl-5-methyl-2-oxo-1(2H)-pyridinyl)hexanoylamino)propanoic acid, (10).
    • Step One: To a solution of (R)-(+)-2-bromohexanoic acid (410 mg, 2.1 mmol) and NMM (0.265 mL, 2.1 mmol) in THF ( 8 mL) at 0 °C under a dry, nitrogen atmosphere, isobutyl chloroformate (0.27 mL, 2.1 mmol) was added. The resulting suspension was stirred at 0 °C for 10 minutes before the addition of a solution of 6 (500 mg, 2.1 mmol) in DMF (2 mL). After 1 hour the suspension was filtered and the filtrate was concentrated under reduced pressure. The residue was taken up in CH2Cl2 and washed with HCl (1 N, 2 times). The combined organic layers were washed with brine. The organic layer was dried over MgSO4, filtered and concentrated under reduced pressure to give 59 (840 mg, 96% yield) as a yellow oil. This material was used without further purification.
    • Step Two: To a solution of 2-fluoro-5-methylpyridine (3.23 g, 30 mmol) in THF (60 mL) cooled to -78 °C under a dry, nitrogen atmosphere, lithium diisopropylamide (22 mL, 2 M solution in THF, 44 mmol) was added dropwise. The resulting orange-red solution was stirred at -78 °C for 6 hours after which benzaldehyde (3.1 mL, 35 mmol) was added. The reaction mixture was stirred an additional 30 minutes, quenched with H2O(75 mL) and extracted with EtOAc (2 times). The combined organic layers were washed with brine, dried over MgSO4, filtered and concentrated under reduced pressure to give 60 (6.5 g, quant.) as a yellow oil. This material was used without further purification.
    • Step Three: A solution of 60 (6.5 g, 30 mmol), boron trifluoride diethyl etherate (13 mL, 100 mmol) and triethylsilane (9 mL, 60 mmol) in dichloroethane (50 mL) was heated to reflux under a dry, nitrogen atmosphere and for 1 hour. The resulting solution was allowed to cocl to room temperature and quenched with H2O(50 mL). The resulting mixture was extracted with EtOAc (2 times). The combined organic layers were washed with brine, dried over MgSO4, filtered and concentrated under reduced pressure to give 61 (5.9 g, 98 % yield) as a yellow oil.
    • Step Four: A solution of 61 (5.9 g, 30 mmol) in dioxane (2 mL) was added to HCl (6 N, 50 mL) and the resulting mixture was heated to reflux for 12 hours. The resulting solution was allowed to cool to room temperature and made basic by the addition of NaOH (2 N). The resulting mixture was extracted with EtOAc (100 mL x 2) and the combined organic layers were washed with brine, dried over MgSO4 and filtered. The resulting filtrate was concentrated under reduced pressure. The residue was recrystallized from methanol/hexanes to provide 62 (3.1 g, 51% yield) as an off-white solid.
    • Step Five: To a solution of 62 (48 mg, 0.24 mmol) in DME (1.5 mL) under a dry, nitrogen atmosphere cooled to -40 °C, NaHMDS (0.25 mL, 1M in THF, 0.25 mmol) was added. The resulting suspension was stirred at -40 °C for an additional 30 minutes before LiBr (21 mg, 0.25 mmol) was added. After an additional 10 minutes, a solution of 59 (100 mg, 0.24 mmol) in DMF (0.5 mL) was added dropwise. The resulting mixture was then allowed to warm to room temperature and then was heated to 45 °C for 3.5 hours. The mixture was allowed to cool to room temperature and quenched with HCl (1 N, 15 mL). The resulting mixture was extracted with CH2Cl2 (twice). The combined organic layers were washed with aqueous sodium carbonate (5%) and brine. The organic phase was dried over MgSO4, filtered and concentrated under reduced pressure. The residue was recrystallized from methanol/hexanes to give 63 (39 mg, 31 %) as white crystals.
  • (3S)-3-(1,3-benzodioxol-5-yl-3-((2S)-2-(3-benzyl-5-methyl-2-oxo-1(2H)-pyridinyl)hexanoylamino)propanoic acid, (10),was prepared from 63 according to procedures described in Example 1.
  • Among the compounds representative of the present invention, which can be synthesized according to the procedure of Example 22, by varying starting materials, are (3S)-3-{[(2S)-2-(3-benzyl-5-methyl-2-oxopyridin-1(2H)-yl)hexanoyl]amino}-3-(3',4'-dimethoxy-1,1'-biphenyl-4-yl)propanoic acid, (3S)-3-({(2S)-2-[3-(2-chlorobenzyl)-5-methyl-2-oxopyridin-1(2H)-yl]hexanoyl}amino)-3-(3',4'-dimethoxy-1,1'-biphenyl-4-yl)propanoic acid, (3S)-3-(1,1'-biphenyl-4-yl)-3-({(2S)-2-[3-(2-chloro-6-methylbenzyl)-5-methyl-2-oxopyridin-1(2H)-yl]hexanoyl}amino)propanoic acid, (3S)-3-[(2S)-2-(3-benzyl-5-methyl-2-oxopyridin-1(2H)-yl)hexanoyl]amino}-3-(1,1'-biphenyl-4-yl)propanoic acid, (3S)-3-(1,1'-biphenyl-4-yl)-3-({(2S)-2-[3-(2-chlorobenzyl)-5-methyl-2-oxopyridin-1(2H)-yl]hexanoyl}amino)propanoic acid, (3S)-3-{[(2S)-2-(3-benzyl-5-methyl-2-oxopyridin-(2H)-yl)hexanoyl]amino}-3-(4'-methyl-1,1'-biphenyl-4-yl)propanoic acid, (3S)-3-({(2S)-2-[3-(2-chlorobenzyl)-5-methyl-2-oxopyridin-1(2H)-yl]hexanoyl}amino)-3-(4'-methyl-1,1'-biphenyl-4-yl)propanoic acid, (3S)-3-({(2S)-2-[3-(2-chloro-6-methylbenzyl)-5-methyl-2-oxopyridin-1(2H)-yl]hexanoyl}amino)-3-(4'-methyl-1,1'-biphenyl-4-yl)propanoic acid, (3S)-3-{[(2S)-2-(3-benzyl-5-methyl-2-oxopyridin-1(2H)-yl)hexanoyl]amino}-3-(2',6'-dimethoxy-1,1'-biphenyl-4-yl)propanoic acid, (3S)-3-({(2S)-2-[3-(2-chlorobenzyl)-5-methyl-2-oxopyridin-1(2H)-yl]hexanoyl}amino)-3-(2',6'-dimethoxy-1,1'-biphenyl-4-yl)propanoic acid, (3S)-3-({(2S)-2-[3-(2-chloro-6-methylbenzyl)-5-methyl-2-oxopyridin-1(2H)-yl]hexanoyl}amino)-3-(2',6'-dimethoxy-1,1'-biphenyl-4-yl)propanoic acid, (3S)-3-{[(2S)-2-(3-benzyl-5-methyl-2-oxopyridin-1(2H)-yl)hexanoyl]amino}-3-(1,1'-biphenyl-3-yl)propanoic acid, (3S)-3-(1,1'-biphenyl-3-yl)-3-({(2S)-2-[3-(2-chlorobenzyl)-5-methyl-2-oxopyridin-1(2H)-yl]hexanoyl}amino)propanoic acid, (3S)-3-(1,1'-biphenyl-3-yl)-3-({(2S)-2-[3-(2-chloro-6-methylbenzyl)-5-methyl-2-oxopyridin-1(2H)-yl]hexanoyl}amino)propanoic acid, (3S)-3-{[(2S)-2-(3-benzyl-5-methyl-2-oxopyridin-1(2H)-yl)hexanoy]amino}-3-(2'-methoxy-1,1'-biphenyl-3-yl)propanoic acid, (3S)-3-({(2S)-2-[3-(2-chlorobenzyl)-5-methyl-2-oxopyridin-1(2H)-yl]hexanoyl}amino)-3-(2'-methoxy-1,1'-biphenyl-3-yl)propanoic acid, (3S)-3-({(2S)-2-[3-(2-chloro-6-methylbenzyl)-5-methyl-2-oxopyridin-1(2H)-yl]hexanoyl}amino)-3-(2'-methoxy-1,1'-biphenyl-3-yl)propanoic acid, (3S)-3-({(2S)-2-[3-(2-fluoro-6-methoxybenzyl)-5-methyl-2-oxopyridin-1(2H)-yl]hexanoyl}amino)-3-(4-methylphenyl)propanoic acid, (3S)-3-({(2S)-2-[3-(2,6-dimethylbenzyl)-5-methyl-2-oxopyridin-1(2H)-yl]hexanoyl}amino)-3-(4-methylphenyl)propanoic acid, (3S)-3-({(2S)-2-[3-(3,5-dimethylbenzyl)-5-methyl-2-oxopyridin-1(2H)-yl]hexanoyl}amino)-3-(4-methylphenyl)propanoic acid, (3S)-3-({(2S)-2-[3-(2,6-dichlorobenzyl)-5-methyl-2-oxopyridin-1(2H)-yl]hexanoyl}amino)-3-(4-methylphenyl)propanoic acid, (3S)-3-({(2S)-2-[3-(2-chloro-6-fluorobenzyl)-5-methyl-2-oxopyridin-1(2H)-yl]hexanoyl}amino)-3-(4-methylphenyl)propanoic acid, (3S)-3-({(2S)-2-[3-(2,6-difluorobenzyl)-5-methyl-2-oxopyridin-1(2H)-yl]hexanoyl}amino)-3-(4-methylphenyl)propanoic acid, (3S)-3-(1,3-benzodioxol-5-yl)-3-({(2S)-2-[3-(2,6-difluorobenzyl)-5-methyl-2-oxopyridin-1(2H)-yl]hexanoyl}amino)propanoic acid, (3S)-3-(1,3-benzodioxol-5-yl)-3-({(2S)-2-[3-(2-chloro-6-fluorobenzyl)-5-methyl-2-oxopyridin-1(2H)-yl]hexanoyl}amino)propanoic acid, (3S)-3-(1,3-benzodioxol-5-yl)-3-({(2S)-2-[3-(2,6-dichlorobenzyl)-5-methyl-2-oxopyridin-1(2H)-yl]hexanoyl}amino)propanoic acid, (3S)-3-(1,3-benzodioxol-5-yl)-3-({(2S)-2-[3-(2,6-dimethylbenzyl)-5-methyl-2-oxopyridin-1(2H)-yl]hexanoyl}amino)propanoic acid, (3S)-3-(1,3-benzodioxol-S-yl)-3-({(2S)-2-[3-(3,5-dimethylbenzyl)-5-methyl-2-oxopyridin-1(2H)-yl]hexanoyl}amino)propanoic acid, (3S)-3-(1,3-benzodioxol-5-yl)-3-({(2S)-2-[3-(2-fluoro-6-methoxybenzyl)-5-methyl-2-oxopyridin-1(2H)-yl]hexanoyl}amino)propanoic acid, (3S)-3-({(2S)-2-[3-(2-chlorobenzyl)-5-methyl-2-oxopyridin-1(2H)-yl]hexanoyl}amino)-3-(3,4-diethoxyphenyl)propanoic acid, (3S)-3-(3,4-diethoxyphenyl)-3-({(2S)-2-[3-(2,6-difluorobenzyl)-5-methyl-2-oxopyridin-1(2H)-yl]hexanoyl}amino)propanoic acid, (3S)-3-({(2S)-2-[3-(2,6-difluorobenzyl)-5-methyl-2-oxopyridin-1(2H)-yl]hexanoyl}amino)-3-(3-ethoxyphenyl)propanoic acid, (3S)-3-({(2S)-2-[3-(2-chloro-6-fluorobenzyl)-5-methyl-2-oxopyridin-1(2H)-yl]hexanoyl}amino)-3-(3-ethoxyphenyl)propanoic acid(3S)-3-({(2S)-2-[3-(2-chlorobenzyl)-5-methyl-2-oxopyridin-1(2H)-yl]-3-methylbutanoyl}amino)-3-(4-methylphenyl)propanoic acid, (3S)-3-({(2S)-2-[3-(2-chlorobenzyl)-5-methyl-2-oxopyridin-1(2H)-yl]-4-methylpentanoyl}amino)-3-(4-methylphenyl)propanoic acid, (3S)-3-(1,3-benzodioxol-5-yl)-3-({(2S)-2-[3-(2-chlorobenzyl)-5-methyl-2-oxopyridin-1(2H)-yl]-4-methylpentanoyl}amino)propanoic acid, (3S)-3-(1,3-benzodioxol-5-yl)-3-({(2S)-2-[3-(2-chlorobenzyl)-5-methyl-2-oxopyridin-1(2H)-yl]-3-methylbutanoyl}amino)propanoic acid, (3S)-3-(1,3-benzodioxol-5-yl)-3-({(2S)-2-[3-(2-chlorobenzyl)-5-methyl-2-oxopyridin-1(2H)-yl]-3-phenylpropanoyl}amino)propanoic acid, (3S)-3-(1,3-benzodioxol-5-yl)-3-(((2R)-2-(1-benzyl-5-methyl-2-oxo-1,2-dihydropyridin-3-yl)hexanoyl)amino) propanoic acid and (3S)-3-({(2S)-2-[3-(2-chlorobenzyl)-5-methyl-2-oxopyridin-1(2H)-yl]-3-phenylpropanoyl}amino)-3-(4-methylphenyl)propanoic acid.
    • Example 23 Synthesis of (3S)-3-(1,3-benzodioxol-5-yl)-3-{[(2R)-2-(3-benzyl-4-hydroxy-5-methyl-2-oxopyridin-1(2H)-yl)hexanoyl]amino}propanoic acid, 67, and (3S)-3-(1,3-benzodioxol-5-yl)-3-{[(2S)-2-(3-benzyl-4-hydroxy-5-methyl-2-oxopyridin-1(2H)-yl)hexanoyl]amino}propanoic acid, 68.
    • Step One: To a solution of methyl propionylacetate (2.00g 15.4 mmol) in anhydrous THF (62 mL) cooled to 0 °C under a dry nitrogen atmosphere, sodium hydride (60% dispersion in mineral oil, 0.644g, 16.1 mmol) was added in two portions. The resulting mixture was stirred for 15 minutes at 0 °C, benzyl bromide (2.75g, 16.1 mmol) was added by syringe then the mixture was allowed to warm to room temperature overnight. The resulting mixture was poured into HCl (2N) and extracted with ethyl acetate. The organic layer was washed with brine, dried over Mg SO4 and filtered and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel chromatography, eluting with 9:1 hexanes:ethyl acetate to give 64 (2.86 g, 84% yield).
    • Step Two: To a suspension of sodium hydride (60% dispersion in mineral oil, 0.623g, 15.6 mmol) in THF, (52 mL) at room temperature under a dry nitrogen atmosphere, N,N,N',N'-tetramethylethylenediamine (2.10 mL, 13.6 mmol) was added. The resulting suspension was cooled to -20 °C and a solution of 64 (286g, 13.0 mmol) in THF (5 mL) was added slowly. The mixture was allowed to warm to room temperature, stirred for 10 minutes then was cooled to -20 °C. To the resulting solution, n-butyllithium (1.6M in hexanes, 15.4 mL, 24.9 mmol) was added dropwise by syringe. The mixture was stirred at -20 °C for an additional 15 minutes, then quenched with the rapid addition of methyl formate (1.00 mL, 16.2 mmol) via syringe and the mixture was allowed to stir for an additional 15 minutes. The reaction was cautiously quenched with excess aqueous HCl (2N) and diluted with hexanes. The hexanes layer is washed with brine, dried over MgSO4, filtered and concentrated under reduced pressure to give 65 (1.10g, 34%) as a yellow oil. This material was used without further purification.
    • Step Three: A solution of 65 (0.75g, 3.0 mmol) and 23 (0.75 g, 2.1 mmol) in methanol (30 mL, 0.1M) was heated at 45 °C under nitrogen for 1 hour before refluxing, overnight. The mixture was cooled and concentrated to dryness. The residue was purified by silica gel chromatography, eluting with 2:1 hexarnes/ethyl acetate, increasing to ethyl acetate to give 66 (0.40 g, 35% yield) as a white foam.
    • Step Four: To a solution of 66 (0.40 g, 0.73 mmol) in THF (3 mL) at room temperature, aqueous NaOH (1 mL) and methanol (2 mL) were added. The resulting solution was stirred for 15 minutes, diluted with water and extracted with ethyl ether. The aqueous layer was acidified with HCl (2N) and extracted with ethyl acetate. The ethyl acetate layer was washed with water and brine, dried over MgSO4 and filtered. The filtrate was concentrated under reduced pressure and the residue was purified by reverse phase HPLC (A: 19:1 H2O:CH3CN +0.1% TFA; B:19:1 CH3CN:H2O + 0.1 %TFA; gradient elution 30% B to 100% B in 31 minutes; 254 nM). The fractions containing each of the diastereomers were separately diluted with water and extracted with ethyl acetate. The ethyl acetate layers were separately washed with water (3 times) and brine, dried over MgSO4 and filtered and the filtrates were separately concentrated under reduced pressure to give (3S)-3-(1,3-benzodioxol-5-yl)-3-{[(2R)-2-(3-benzyl-4-hydroxy-5-methyl-2-oxopyridin-1(2H)-yl)hexanoyl]amino}propanoic acid, 67, (18 mg, 5% yield) and (3S)-3-(1,3-benzodioxol-5-yl)-3-{[(2S)-2-(3-benzyl-4-hydroxy-5-methyl-2-oxopyridin-1(2H)-yl)hexanoyl]amino}propanoic acid, 68, (105 mg, 28% yield). MS for 67: Calculated (M+H)+ = 521.23; Found (M+H)+ = 520.97. MS for 68: Calculated (M+H)+ = 521.23; Found (M+H)+ = 520.95.
    Example 24 Synthesis of (3S)-3-(3-isopropoxyphenyl)-3-({2-[2-oxo-4-(2-phenylethyl)pyridin-1(2H)-yl]hexanoyl}amino)propanoic acid.
    • Step One: To a solution of diisopropylamine (2.94 g, 29.1 mmol) in THF (20 mL) cooled to -78 °C under a dry nitrogen atmosphere, butyllithium (12.8 mL of a 2.5 M solution in hexanes, 32.0 mmol) was added by syringe and stirred at -78 °C for 15 minutes. The solution was added by cannula to a solution of 2-fluoro-4-methyl-pyridine (2.15 g, 9.40 mmol) in THF (20 mL) cooled to -78 °C under a dry nitrogen atmosphere. The resulting mixture was stirred at -78 °C for 4 hours, and then quenched with benzaldehyde (2.17 mL, 21.3 mmol). The resulting yellow solution was warmed to room temperature, diluted with water and extracted with ethyl acetate. The organic layer was washed with brine, dried over MgSO4 and filtered. The filtrate was concentrated under reduced pressure and the residue was purified by silica gel chromatography, eluting with 7:3 hexanes:ethyl acetate to give 69 (1.92 g, 94%) as a yellow oil.
    • Step Two: To a solution of 69 (1.92 g, 8.84 mmol) in anhydrous methanol (20 mL) at room temperature under a dry nitrogen atmosphere, palladium on charcoal (1.00 g, 10% Pd dry weight basis, Degussa type E101 NE/W, wet, 50% water by weight) and four drops of glacial acetic acid were added. The nitrogen atmosphere was replaced by hydrogen (alternate five times between vacuum and hydrogen supplied by balloon) and the mixture was stirred at room temperature overnight. The mixture was filtered through Celite® 521 and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel chromatography, eluting with 8:2 hexanes:ethyl acetate to give 70 (0.98 g, 55%) as a white solid.
    • Step Three: To a solution of 70 (0.90 g, 4.47 mmol) in hydrogen chloride (2 mL, 4.0 M in dioxane, 8.0 mmol) at room temperature, aqueous hydrogen chloride (6.0 M, 40 mL) was added and the mixture was refluxed for 3 hours. The solution was cooled to room temperature, made basic with aqueous sodium hydroxide (2N), and extracted with ethyl acetate. The organic layer was washed with brine, dried over MgSO4 and filtered. The filtrate was concentrated under reduced pressure to give 71 (0.81 g, 91 %) as a pale yellow solid. This material was used without purification
    • Step Four: To a solution of 71 (0.20 g, 1.0 mmol) in methyl sulfoxide (4.0 mL) at room temperature, sodium hydride (60% w/w dispersion in mineral oil, 0.12 g, 3.0 mmol) was added. The mixture was stirred at room temperature under a dry nitrogen atmosphere for 1 hour. To the resulting mixture, ethyl 2-bromohexanoate (0.18 mL, 1.0 mmol) was added and the mixture was stirred for 30 minutes. The mixture was quenched with HCl (2N, 50 mL) and extracted with ethyl acetate. The organic layer was washed with brine, dried over MgSO4 and filtered. The filtrate was concentrated under reduced pressure and the residue was purified by silica gel chromatography, eluting with 9:1 hexanes:ethyl acetate, increasing to 8:2 hexanes:ethyl acetate to give 72 (0.19 g, 0.55 mmol) as a solid.
  • (3S)-3-(3-isopropoxyphenyl)-3-({2-[2-oxo-4-(2-phenylethyl)pyridin-1(2H)-yl]hexanoyl}amino)propanoic acid was prepared from 72 according to procedures described in Example 1. MS: Calculated (M-H)- = 517.27; Found (M-H)- = 517.21.
    • Example 25 Synthesis of (3S)-3-[3-(difluoromethyl)phenyl]-3-({2-[5-methyl-2-oxo-3-(phenylmethyl)-1(2H)-pyridinyl]hexanoyl}amino)propanoic acid.
    • Step One: To a solution of 3-bromobenzaldehyde, 73, (3.00 g, 16.2 mmol) in DMF (69 mL) under a dry nitrogen atmosphere, palladium acetate (73 mg, 0.32 mmol), tri-o-tolylphosphine (197 mg, 0.65 mmol), ethyl acrylate (2.20 mL, 20.3 mmol) and triethylamine (4.50 mL, 32.4 mmol) were added. The system was deoxygenated (toggle between vacuum and nitrogen five times), the mixture was heated to 125 °C for 19 hours and then cooled to room temperature. The reaction was poured into water and extracted with ether. The organic layer was washed with HCl (4N) and brine, dried over MgSO4 and filtered. The filtrate was concentrated under reduced pressure to give 74 (2.74g, 83%), which was used without further purification.
    • Step Two: To a flask containing 74 (1.00 g, 4.9 mmol) under a dry nitrogen atmosphere, (dimethylamino)sulfur trifluoride (0.96 mL, 9.8 mmol) was added by syringe. The mixture was heated to 90 °C behind a blast shield for 25 minutes then was cooled to room temperature. The resulting mixture was diluted with CH2Cl2 and washed with saturated aqueous NaHCO3 and H2O. The organic layer was dried over MgSO4 and filtered and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel chromatography, eluting with 1:5 ethyl actetate:hexanes to give 75 (0.62 g, 56%).
    • Step Three: To a solution of (R)-(+)-N-benzyl-α-methylbenzylamine (0.70 g, 3.3 mmol) in THF (6.7 mL) cooled to -78 °C under a dry nitrogen atmosphere, sec-BuLi (4.22 mL, 1.3M in cyclohexane, 5.5 mmol) was added dropwise. The resulting mixture was stirred at -78 °C for 30 minutes and then a solution of 75 (0.62 g, 2.74 mmol) in THF (3.4 mL) was added dropwise by syringe. The mixture was stirred at -78 °C for 5 hours and then quenched with glacial AcOH (2 mL) in THF (5 mL). The reaction mixture was warmed to room temperature, poured into a 1:1 mixture of saturated aqueous NaHCO3:EtOAc. The organic layer was washed with H2O (2 times) and brine, dried over MgSO4 and filtered. The filtrate was concentrated under reduced pressure and the residue was purified by silica gel chromatography, eluting with 1:5 ethyl actetate:hexanes to give 76 (1.2 g, 100%). This material still contained minor impurities but was used without further purification.
    • Step Four: To a solution of 76 (0.50 g, 1.14 mmol) in EtOH (10 mL) at room temperature under a dry nitrogen atmosphere, Pd/C (10% Pd dry weight basis, 50% water by weight, Degussa type E101 NE/W, 0.25 g) and glacial AcOH (0.5 mL) were added. The atmosphere was replaced by hydrogen (toggle between vacuum and hydrogen from a balloon five times) and the mixture was heated to 35 °C for 6 hours. The reaction was cooled to room temperature, filtered through a plug of Celite U 521 and the filtrate was concentrated under reduced pressure. The residue was diluted with CHCl3 and washed with saturated aqueous NaHCO3. The aqueous layer was extracted with CHCl3 (2 times) and the combined organic layers were dried over MgSO4 and filtered. The filtrate was concentrated under reduced pressure and the residue was purified by silica gel chromatography, eluting with 1:10 MeOH:CHCl3 to give 77(180mg, 67%).
  • (03S)-3-[3-(difluoromethyl)phenyl]-3-({2-[5-methyl-2-oxo-3-(phenylmethyl)-1(2H)-pyridinyl]hexanoyl}amino)propanoic acid was synthesized from 77 according to procedures described in Example 1. MS: Calculated (M-H)- = 509.23; Found (M-H)- = 509.19.
    • Example 26
  • The ability of compounds of the present invention to inhibit binding is determined by a procedure in which a 26-amino acid peptide containing the CS 1 sequence of fibronectin with an N-terminal Cys (CDELPQLVTLPHPNLHGPEILDVPST) was coupled to maleimide activated ovalbumin. Bovine serum albumin (BSA) and CS 1 conjugated ovalbumin were coated onto 96-well polystyrene plates at 0.5 mg/ml in TBS (50 mM Tris, pH 7.5; 150 mM NaCl) at 4°C for 16 hours. The plates were washed three times with TBS and blocked with TBS containing 3% BSA at room temperature for 4 hours. Blocked plates were washed three times in binding buffer (TBS; 1 mM MgCl2; 1 mM CaCl2; 1 mM MnCl2) prior to assay. Ramos cells fluorescently labeled with calcein AM were resuspended in binding buffer (107 cells/ml) and diluted 1:2 with same buffer with or without compound. The cells were added immediately to the wells (2.5 x 105 cells/well) and incubated for 30 minutes at 37°C. Following three washes with binding buffer, adherent cells were lysed and quantitated using a fluorometer. The results are shown in Tables 1, 2, 3 and 4. IC50 is defined as the dose required to give 50% inhibition. MS in Table 3 stands for Mass Spec. nd stands for not determined in the Tables. A stands for inhibition in Table 2, and the percent inhibition indicates the inhibition of cell adhesion when compound is included in the assay at a concentration of 100 [µM. The lower the IC50 value and the greater the percentage of inhibition, the more efficient the compound is at prevention of cell adhesion. Table 1
    Compound Number IC50 (nM) Mass Spectral Data (m/z)
    8 7 Calc'd (M-H)- = 503.22
    Found (M-H)- = 503.24
    9 2000 Calc'd (M-H)- = 503.22
    Found (M-H)- = 503.24
    10 3 Calc'd (M-H)- = 503.22
    Found (M-H)- = 503.22
    12 40 Calc'd (M-H)- = 501.24
    Found (M-H)- = 501.27
    13 70 Calc'd (M-H)- = 473.24
    Found (M-H)- = 473.26
    14 150 Calc'd (M-H)- = 477.22
    Found (M-H)- = 477.25
    15 30 Calc'd (M+H)+ = 535.25
    Found (M+H)+ = 535.00
    16 35 Calc'd (M+H)- = 519.25
    Found (M+H) = 519.18
    17 60 Calc'd (M-H)- = 521.21
    Found (M-H)- = 521.22
    19 6 Calc'd (M-H)- = 537.18
    Found (M-H)- = 537.22
    Table 2
    Compound IC50 (µM) % A Mass Spectral Data (m/z)
    (3S)-3-(1,3-benzodioxol-5-yl)-3-({(2S)-2-[2-oxo-3-(2-thienylmethyl)-1-imidazolidinyl]hexanoyl}amino)propanoic acid 0.15 100 Calc'd(M-H)-= 486.37
    Found (M-H)-= 486.20
    (3S)-3-(1,3-benzodioxol-5-yl)-3-(((2S)-2-(2-oxo-3-(2-thienylmethyl)tetrahydro-1(2H)-pyrimidinyl)hexanoyl)amino)propanoic acid 0.005 100 Calc'd (M-H)- = 500.18
    Found (M-H)-= 500.22
    (3S)-3-(1,3-benzodioxol-5-yl)-3-(((2S)-2-(2-oxo-4-(2-thienyl)-3-(2-thienylmethyl)tetrahydro-1(2H)-pyrimidinyl)hexanoyl)amino)propanoic acid 0.05 100 Calc'd (M-H)-= 582.17
    Found (M-H)- = 582.21
    (3S)-3-(1,3-benzodioxol-5-yl)-3-({(2S)-2-[2-oxo-3-(2-thienylmethyl)-1,3-diazepan-1-yl)hexanoyl} amino)propanoic acid nd nd nd
    Table 3
    Compound Mass Spectral Data (m/z) IC50 (µM)
    (3S)-3-(1,3-benzodioxol-5-yl)-3-({(2S)-2-[2,5-dioxo-1-(2-thiophenylmethyl)-1,2,3,5-tetrahydro-4H-1,4-benzodiazepin-4-yl]hexanoyl} amino)propanoic acid Calc'd (M-H)- = 576.18
    Found (M-H)- = 576.18    		 1.5
    (3S)-3-(1,3-benzodioxol-5-yl)-3-({(2S)-2-[(3S)-2,5-dioxo-3-(phenylmethyl)-4-(2-thiophenylmethyl)tetrahydro-1(2H)- pyrazinyl]hexanoyl}amino)propanoic acid Calc'd (M-H)- = 604.21
    Found (M-H)- = 604.24    		 6
    (3S)-3-(1,3-benzodioxol-5-yl)-3-({2-[3-(phenyloxy)phenyl]acetyl}amino)propanoic acid Calc'd (M-H)- = 418.11
    Found (M-H)- = 418.12    		 >100
    (3S)-3-(1,3-benzodioxol-5-yl)-3-({2-[2-oxo-3-[(2-thiophenylmethyl)amino]-1(2H)-pyridinyl]hexanoyl}amino)propanoic acid Calc'd (M-H)-= 510.17
    Found (M-H)- = 510.21    		 1.3
    (3S)-3-(1,3-benzodioxol-5-yl)-3-({2-[2-oxo-3-(phenylmethyl)-2,3-dihydro-1H-benzimidazol-1-yl]acetyl}amino)propanoic acid Calc'd(M-H)- = 472.15
    Found (M-H)- = 472.18    		 0.2
    (3S)-3-(1,3-benzodioxol-5-yl)-3-({2-[2-oxo-3-(phenylmethyl)-2,3-dihydro-1H-benzimidazol-1-yl]hexanoyl}amino)propanoic acid Calc'd (M-H)-= 528.21
    Found (M-H)- = 528.22    		 0.07
    (3S)-3-(1,3-benzodioxol-5-yl)-3-({2-[2-oxo-3-(phenylmethyl)-1(2H)-pyridinyl]butanoyl}amino)propanoic acid Calc'd (M-H)- = 461.17
    Found (M-H)- = 461.18    		 0.03
    (3S)-3-(1,3-benzodioxol-5-yl)-3-({(2S)-2-[2-oxo-3-(phenylcarbonyl)-1(2H)-pyridinyl]hexanoyl}amino)propanoic acid Calc'd (M-H)-= 503.18
    Found (M-H)- = 503.18    		 0.55
    (3S)-3-(1,3-benzodioxol-5-yl)-3-({2-[2-oxo-3-(phenylmethyl)-1(2H)-pyridinyl]acetyl}amino)propanoic acid Calc'd(M-H)- = 433.14
    Found (M-H)-= 433.16    		 0.45
    (3S)-3-(1,3-benzodioxol-5-yl)-3-[({1-[2-oxo-3-(phenylmethyl)-1(2H)-pyridinyl]cyclohexyl}carbonyl)amino] propanoic acid Calc'd(M-H)-= 501.20
    Found (M-H)- = 501.24    		 50
    (3S)-3-(1,3-benzodioxol-5-yl)-3-({(2S)-2-[2-oxo-3-(phenylmethyl)-1(2H)-pyridinyl]hexanoyl}amino)propanoic acid Calc'd (M-H)- = 489.20
    Found (M-H)-= 489.20    		 0.004
    (3S)-3-(1,3-benzodioxol-5-yl)-3-({2-[2-oxo-3-(phenylmethyl)-2,3-dilhydro-1H-imidazol-1-yl]hexanoyl}amino)propanoic acid Calc'd (M-H)- = 478.20
    Found (M-H)- = 478.23    		 0.06
    (3S)-3-(1,3-benzodioxol-5-yl)-3-({(2S)-2-[2,4-dioxo-1-(phenylmethyl)-1,4-dihydro-3(2H)-quinazolinyl]hexanoyl}amino)propanoic acid Calc'd (M-H)- = 556.21
    Found (M-H)- = 556.22    		 0.1
    (3S)-3-(1,3-benzodioxol-5-yl)-3-({2-[3-[(2-chlorophenyl)methyl]-5-methyl-2-oxo-1(2H)-pyridinyl]hexanoyl}amino)propanoic acid Calc'd (M-H)-= 537.18
    Found (M-H)-= 537.22    		 0.01
    (3S)-3-(1,3-benzodioxol-5-yl)-3-({2-[5,5-dimethyl-2,4-dioxo-3-(phenylmethyl)tetrahydro-1H-imidazol-1-yl]hexanoyl}amino)propanoic acid Calc'd (M-H)-= 522.22
    Found (M-H)-= 522.22    		 20
    (3S)-3-(1,3-benzodioxol-5-yl)-3-({2-[2-oxo-5-(phenylmethyl)-1(2H)-pyridinyl]hexanoyl}amino)propanoic acid Calc'd (M-H)- = 489.20
    Found (M-H)- = 489.21    		 0.04
    (3S)-3-(1,3-benzodioxol-5-yl)-3-({2-[2-oxo-3-(phenylmethyl)-1(2H)-quinoxalinyl]hexanoyl}amino)propanoic acid Calc'd (M-H)-= 540.21
    Found (M-H)- = 540.21    		 100
    (3S)-3-(1,3-benzodioxol-5-yl)-3-({2-[2-oxo-3-(phenylmethyl)-1(2H)-pyridinyl]pentanoyl}amino)propanoic acid Calc'd (M-H)- = 475.18
    Found (M-H)- = 475.19    		 0.06
    (3S)-3-(1,3-benzodioxol-5-yl)-3-({2-[3-methyl-6-oxo-5-(phenylmethyl)-1(6H)-pyridazinyl]hexanoyl}amino)propanoic acid Calc'd (M-H)- = 504.21
    Found (M-H)- = 504.24    		 0.06
    (3S)-3-(1,3-benzodioxol-5-yl)-3-({2-[2-oxo-3-(phenylmethyl)-3,4-dihydro-1(2H)-quinazolinyl]hexanoyl}amino)propanoic acid Calc'd (M-H)-= 542.23
    Found (M-H)-= 542.26    		 0.4
    (3S)-3-(1,3-benzodioxol-5-yl)-3-({2-[2-oxo-3-(phenylmethyl)-1(2H)-quinolinyl]hexanoyl}amino)propanoic acid Calc'd (M-H)- = 539.22
    Found (M-H)- = 539.22    		 2
    Table 4
    Compound IC50 (nM) Mass Spectral Data (m/z)
    (3S)-3-{[(2S)-2-(3-benzyl-5-methyl-2-oxopyridin-1(2H)-yl)hexanoyl]amino}-3-(3,5-dimethoxyphenyl)propanoic acid 10 Measured (M-H)- = 519.25;
    Calculated (M-H)- = 519.25.
    (3S)-3-{[(2S)-2-(3-benzyl-5-methyl-2-oxopyridin-1(2H)-yl)hexanoyl]amino}-3-(3-fluoro-4-methoxyphenyl)propanoic acid 17 Measured (M-H)- = 507.13;
    Calculated (M-H)- = 507.23.
    (3S)-3-(1,3-benzodioxol-5-yl)-3-{[2-(3-benzyl-2-oxopyridin-1(2H)-yl)hexanoyl]amino}propanoic acid 30 Measured (M-H)- = 489.17;
    Calculated (M-H)- = 489.20.
    (3S)-3-{[2-(3-benzyl-5-methyl-2-oxopyridin-1(2H)-yl)hexanoyl]amino}-3-(3-propoxyphenyl)propanoic acid 10 Measured (M-H)-= 517.19;
    Calculated (M-H)- = 517.27.
    (3S)-3-{[2-(3-benzyl-2-oxopyridin-1(2H)-yl)hexanoyl]amino}-3-(4-methoxy-2,3-dimethylphenyl)propanoic acid 300 Measured (M+H)+= 504.94;
    Calculated (M+H)+ = 505.27.
    (3S)-3-{[(2S)-2-(3-benzyl-5-methyl-2-oxopyridin-1(2H)-yl)hexanoyl]amino}-3-(2',6'-dimethoxy-1,1'-biphenyl-4-yl)propanoic acid 200 Measured (M-H)- = 595.18;
    Calculated (M-H)- = 595.28.
    (3S)-3-{[2-(3-benzyl-5-methyl-2-oxopyridin-1(2H)-yl)hexanoyl]amino}-3-(3,4-dimethylphenyl)propanoic acid 130 Measured (M-H)- = 487.24;
    Calculated (M-H)- = 487.26.
    (3S)-3-{[2-(3-benzyl-5-methyl-2-oxopyridin-1(2H)-yl)hexanoyl]amino}-3-(3-ethoxyphenyl)propanoic acid 35 Measured (M+H)+ = 504.99;
    Calculated (M+H)+ = 505.27.
    (3S)-3-[2-(3-benzyl-5-methyl-2-oxopyridin-1(2H)-yl)hexanoyl]amino}-3-(3,4,5-trimethoxyphenyl)propanoic acid 33 Measured (M+H)+ = 550.93;
    Calculated (M+H)+ = 551.28.
    (3S)-3-{[2-(3-benzyl-5-methyl-2-oxopyridin-1(2H)-yl)hexanoyl]amino}-3-(4-methoxy-3,5-dimethylphenyl)propanoic acid 140 Measured (M+H)+ = 518.98;
    Calculated (M+H)+ = 519.29.
    (3S)-3-{[2-(3-benzyl-5-methyl-2-oxopyridin-1(2H)-yl)hexanoyl]amino}-3-(6-methoxy-2-naphthyl)propanoic acid 40 Measured (M+H)+ = 540.98;
    Calculated (M+H)+ = 541.27.
    (3S)-3-{[2-(3-benzyl-5-methyl-2-oxopyridin-1(2H)-yl)hexanoyl]amino}-3-(3-butoxyphenyl)propanoic acid 45 Measured (M+H)+ = 533.03;
    Calculated (M+H)+= 533.30.
    (3S)-3-(1,3-benzodioxol-5-yl)-3-{[(2S)-2-(3-benzyl-4-hydroxy-5-methyl-2-oxopyridin-1(2H)-yl)hexanoyl]amino}propanoic acid 200 Measured (M+H)+ = 520.97;
    Calculated (M+H)+ 521.23.
    (3S)-3-(1,3-benzodioxol-5-yl)-3-{[(2R)-2-(3-benzyl-4-hydroxy-5-methyl-2-oxopyridin-1(2H)-yl)hexanoyl]amino}propanoic acid 2000 Measured (M+H)+ = 520.95;
    Calculated (M+H)+= 521.23.
    (3S)-3-{[2-(3-benzyl-5-methyl-2-oxopyridin-1(2H)-yl)hexanoyl]amino}-3-(3-isopropoxyphenyl)propanoic acid 4 Measured (M+H)+ = 518.99;
    Calculated (M+H)+ = 519.29.
    (3S)-3-({2-[3-(2,6-dichlorobenzyl)-5-methyl-2-oxopyridin-1(2H)-yl]hexanoyl}amino)-3-(3-isopropoxyphenyl)propanoic acid 275 Calculated (M+H)+= 587.21;
    Found (M+H)+ = 586.95.
    (3S)-3-(3-isopropoxyphenyl)-3-({2-[2-oxo-4-(2-phenylethyl)pyridin-1(2H)-yl]hexanoyl}amino)propanoic acid 95 Calculated (M-H)- = 517.27;
    Found (M-H)- = 517.21.
    (3S)-3-{[2-(3-benzyl-5-methyl-2-oxopyridin-1(2H)-yl)hexanoyl]amino}-3-(3,5-dimethylphenyl)propanoic acid 52 Calculated (M-H)- = 487.26;
    Found(M-H)-=487.20.
    (3S)-3-{[2-(3-benzyl-5-methyl-2-oxopyridin-1(2H)-yl)hexanoyl]amino}-3-(4-methoxy-2,5-dimethylphenyl)propanoic acid 283 Calculated (M-H)- = 517.27;
    Found (M-H)- = 517.20.
    (3S)-3-({2-[3-(3-chlorobenzyl)-5-methyl-2-oxopyridin-1(2H)-yl]hexanoyl}amino)-3-(3-propoxyphenyl)propanoic acid 23 Calculated (M-H)- = 551.23;
    Found (M-H)- = 551.22.
    (3S)-3-{[2-(3-benzyl-5-methyl-2-oxopyridin-1(2H)-yl)hexanoyl]amino}-3-[3-(trifluoromethyl)phenyl]propanoic acid 250 Calculated (M+H)- = 529.23;
    Found (M+H)- = 529.01.
    (3S)-3-{[2-(3-benzyl-5-methyl-2-oxopyridin-1(2H)-yl)hexanoyl]amino}-3-[4-(trifluoromethoxy)phenyl]propanoic acid 27 Calculated (M+H)+ = 545.23;
    Found (M+H)- = 544.97.
    (35)-3-({2-[3-(3-chlorobenzyl)-5-methyl-2-oxopyridin-1(2H)-yl]hexanoyl}amino)-3-(3-isopropoxyphenyl)propanoic acid 20 Calculated (M+H)+ = 553.25;
    Found (M+H)+ = 552.95.
    (3S)-3-({2-[3-(2-ethoxybenzyl)-5-methyl-2-oxopyridin-1(2H)-yl]hexanoyl}amino)-3-(3-isopropoxyphenyl)propanoic acid 19 Calculated (M+H)+ = 563.31;
    Found(M+H)-= 563.17.
    (3S)-3-(3-isopropoxyphenyl)-3-({2-[3-(2-methoxybenzyl)-5-methyl-2-oxopyridin-1(2H)-yl]hexanoyl}amino)propanoic acid 4 Calculated (M+H)- = 549.30;
    Found (M+H)- = 49.13.
    (3S)-3-{[2-(3-benzyl-5-methyl-2-oxopyridin-1(2H)-yl)hexanoyl]amino}-3-[3-(trifluoromethoxy)phenyl]propanoic acid 40 Calculated (M-H)- = 543.21;
    Found (M-H)-= 543.16.
    (3S)-3-{[2-(3-benzyl-5-methyl-2-oxopyridin-1(2H)-yl)hexanoyl]amino}-3-(3-ethoxy-4-methoxyphenyl)propanoic acid 4 Calculated (M-H)- = 533.27;
    Found (M-H)- = 533.22.
    (3S)-3-{[2-(3-benzyl-5-methyl-2-oxopyridin-1(2H)-yl)hexanoyl]amino}-3-(4'-methyl-1,1'-biphenyl-4-yl)propanoic acid 250 Calculated (M-H)- = 549.28;
    Found (M-H)- = 549.16.
    (3S)-3-{[2-(3-benzyl-5-methyl-2-oxopyridin-1(2H)-yl)hexanoyl]amino}-3-(4-chloro-3-isopropoxyphenyl)propanoic acid 25 Calculated (M-H)- = 551.23;
    Found (M-H)- = 551.20.
    (3S)-3-{[2-(3-benzyl-5-methyl-2-oxopyridin-1(2H)-yl)hexanoyl]amino}-3-(4'-methoxy-1,1'-biphenyl-4-yl)propanoic acid 300 Calculated (M-H)- = 565.27;
    Found (M-H)- = 565.21.
    (3S)-3-{[2-(3-benzyl-5-methyl-2-oxopyridin-1(2H)-yl)hexanoyl]amino}-3-(4-methoxy-3-methylphenyl)propanoic acid 9 Calculated (M-H)- = 503.25;
    Found (M-H)- = 503.20.
    (3S)-3-{[2-(3-benzyl-5-methyl-2-oxopyridin-1(2H)-yl)hexanoyl]amino}-3-phenylpropanoic acid 10 Calculated (M-H)- = 459.23;
    Found (M-H)- = 459.18.
    (3S)-3-{[2-(3-benzyl-5-methyl-2-oxopyridin-1(2H)-yl)hexanoyl]amino}-3-(2,5-dimethylphenyl)propanoic acid 300 Calculated (M-H)- = 487.26;
    Found (M-H)- =487.21.
    [3S)-3-({2-[3-(2-chlorobenzyl)-5-methyl-2-oxopyridin-1(2H)-yl]hexanoyl}amino)-3-(4-methylphenyl)propanoic acid 15 Calculated (M-H)-= 507.21;
    Found (M-H)-= 507.15.
    (3S)-3-({2-[3-(2-chlorobenzyl)-5-methyl-2-oxopyridin-1(2H)-yl]hexanoyl}amino)-3-(3-isopropoxyphenyl)propanoic acid 5 Calculated (M-H)- = 551.23;
    Found (M-H)- = 551.20.
    (3S)-3-({2-[3-(2-chlorobenzyl)-5-methyl-2-oxopyridin-1(2H)-yl]hexanoyl}amino)-3-phenylpropanoic acid 12 Calculated (M-H)- = 493.19;
    Found (M-H)- = 493.12.
    (3S)-3-{[2-(3-benzyl-5-methyl-2-oxopyridin-1(2H)-yl)hexanoyl]amino}-3-(3,5-difluorophenyl)propanoic acid 25 Calculated (M-H)- = 495.21;
    Found(M-H)-=495.14.
    (3S)-3-(2,3-dihydro-1H-inden-5-yl)-3-({2-[5-methyl-2-oxo-3-(phenylmethyl)-1(2H)-pyridinyl]hexanoyl}amino)propanoic acid 63 Calculated (M-H)- = 499.26;
    Found (M-H)- = 499.23.
    (3S)-3-({2-[3-[(2,3-dichlorophenyl)methyl]-5-methyl-2-oxo-1(2H)-pyridinyl]hexanoyl}amino)-3-{3-[(1-methylethyl)oxy]phenyl}propanoic acid 68 Calculated (M+H)+= 586.20;
    Found (M+H)+ = 586.88.
    (3S)-3-[1,1'-biphenyl]-3-yl-3-({2-[5-methyl-2-oxo-3-(phenylmethyl)-1(2H)-pyridinyl]hexanoyl}amino)propanoic acid 250 Calculated (M-H)- = 535.26;
    Found (M-H)- = 535.22.
    (3S)-3-({2-[3-{[2,4-dichloro-6-(methyloxy)phenyl]methyl}-5-methyl-2-oxo-1(2H)-pyridinyl]hexanoyl}amino)-3- {3-[(1-methylethyl)oxy]phenyl}propanoic acid 275 Calculated (M+H)+= 616.21;
    Found (M+H)+= 616.88.
    (3S)-3-(4-ethylphenyl)-3-({2-[5-methyl-2-oxo-3-(phenylmethyl)-1(2H)-pyridinyl]hexanoyl}amino)propanoic acid 40 Calculated (M-H)- = 487.26;
    Found (M-H)- = 487.24.
    (3S)-3-[4-(1-methylethyl)phenyl]-3-({2-[5-methyl-2-oxo-3-(phenylmethyl)-1(2H)-pyridinyl]hexanoyl}amino)propanoic acid 160 Calculated (M-H)- = 501.28;
    Found (M-H)- = 501.27.
    (3S)-3-(1-methyl-1H-indol-6-yl)-3-({2-[5-methyl-2-oxo-3-(phenylmethyl)-1(2H)-pyridinyl]hexanoyl}amino)propanoic acid 10 Calculated (M-H)-= 512.25;
    Found (M-H)- = 512.24.
    (3S)-3-({2-[5-methyl-3-(2-naphthalenylmethyl)-2-oxo-1(2H)-pyridinyl]hexanoyl}amino)-3-(4-methylphenyl)propanoic acid 400 Calculated (M-H)- = 523.26;
    Found (M-H)-= 523.23.
    (3S)-3-{3-[(1-methylethyl)oxy]phenyl}-3-({2-[5-methyl-3-(2-naphthalenylmethyl)-2-oxo-1(2H)-pyridinyl]hexanoyl}amino)propanoic acid 20 Calculated (M-H)- = 567.29;
    Found (M-H)- = 567.26.
    (3S)-3-(2,3-dihydro-1H-inden-5-yl)-3-({2-[5-methyl-3-(2-naphthalenylmethyl)-2-oxo-1(2H)-pyridinyl]hexanoyl}amino)propanoic acid 283 Calculated (M-H)- = 549.28;
    Found (M-H)- = 549.21.
    (3S)-3-({2-[5-methyl-3-(2-naphthalenylmethyl)-2-oxo-1(2H)-pyridinyl]hexanoyl}amino)-3-phenylpropanoic acid 30 Calculated (M-H)- = 509.24;
    Found (M-H)-= 509.19.
    (2S)-2-({2-[5-methyl-2-oxo-3-(phenylmethyl)-1(2H)- pyridinyl]hexanoyl}amino)-3-phenylpropanoic acid > 10000 Calculated (M-H)- = 459.23;
    Found (M-H)- = 459.22.
    (3S)-3-({2-[5-methyl-2-oxo-3-(phenylmethyl)-1(2H)-pyridinyl]hexanoyl}amino)-3-[3-(2-methylpropyl)phenyl]propanoic acid 10 Calculated (M-H)-=515.29;
    Found (M-H)- = 515.28.
    (3S)-3-[3-(diethylamino)phenyl]-3-({2-[5-methyl-2-oxo-3-(phenylmethyl)-1(2H)-pyridinyl]hexanoyl}amino)propanoic acid 10 Calculated (M-H)- = 530.30;
    Found (M-H)- = 530.25.
    (3S)-3-[3-(difluoromethyl)phenyl]-3-({2-[5-methyl-2-oxo-3-(phenylmethyl)-1(2H)-pyridinyl]hexanoyl}amino)propanoic acid 20 Calculated (M-H)- = 509.23;
    Found (M-H)- = 509.19.
    (3S)-3-{3-[(1-methylethyl)oxy]phenyl}-3-({2-[5-methyl-3-[(2-methylphenyl)methyl]-2-oxo-1(2H)-pyridinyl]hexanoyl}amino)propanoic acid 5 Calculated (M+H)+ = 533.30;
    Found (M+H)+ = 532.94.
    (2R)-2-({2-[5-methyl-2-oxo-3-(phenylmethyl)-1(2H)- pyridinyl]hexanoyl}amino)-3-phenylpropanoic acid 5000 Calculated (M-H)- = 459.23;
    Found (M-H)- = 459.22.
    (3S)-3-(3-fluorophenyl)-3-({2-[5-methyl-2-oxo-3-(phenylmethyl)-1(2H)-pyridinyl]hexanoyl}amino)propanoic acid 13 Calculated (M-H)- = 477.21;
    Found (M-H)- = 477.20.
    (2R)-2-({2-[5-methyl-2-oxo-3-(phenylmethyl)-1(2H)- pyridinyl]hexanoyl}amino-2-phenylethanoic acid >10000 Calculated (M-H)- = 445.21;
    Found (M-H)- = 444.94.
    (3S)-3-({2-[3-[(2-chloro-4-fluorophenyl)methyl]-5-methyl-2-oxo-1(2H)-pyridinylhexanoyl}amino)-3-{3-[(1-methylethyl)oxy]phenyl}propanoic acid 17 Calculated (M-H)- = 569.22;
    Found (M-H)-=569.18.
    (3S)-3-({2-[5-methyl-3-[(2-methylphenyl)methyl]-2-oxo-1(2H)-pyridinyl]hexanoyl}amino)-3-phenylpropanoic acid 25 Calculated (M+H)+ = 475.26;
    Found (M+H)+= 474.94.
    (3S)-3-{3-[(1-methylethyl)oxy]phenyl}-3-({2-[5-methyl-2-oxo-1-(phenylmethyl)-1,2-dihydro-3-pyridinyl]-2- phenylacetyl}amino)propanoic acid 10 Calculated (M+H)+ = 539.25;
    Found (M+H)+ = 538.91
    (3S)-3-({2-[5-methyl-3-(1-naphthalenylmethyl)-2-oxo-1(2H)-pyridinyl]hexanoyl}amino)-3-phenylpropanoic acid 350 Calculated (M-H)-= 509:24;
    Found (M-H)- = 509.22.
    (3S)-3-{3-[(1-methylethyl)oxy]phenyl}-3-({2-[5-methyl-3-(1-naphthalenylmethyl)-2-oxo-1(2H)-pyridinyl]hexanoyl}amino)propanoic acid 67 Calculated (M-H)- = 567.29;
    Found (M-H)- = 567.28.
    (3S)-3-{4-methyl-3-[(1-methylethyl)oxy]phenyl}-3-({2-[5-methyl-2-oxo-3-(phenylmethyl)-1(2H)-pyridinyl]hexanoyl}amino)propanoic acid 15 Calculated (M-H)- = 531.29;
    Found (M-H)- = 531.26.
    • SEQUENCE LISTING
    1. (1) GENERAL INFORMATION:
      • (i) APPLICANT: Biediger, Ronald J.; Dupre, Brian; Hamaker, Linda K.; Holland, George W.; Kassir, Jamal M.; Li, Wen; Market, Robert V.; Nguyen, Noel; Scott, Ian L.; Wu, Chengde; and Decker, E. Radford.
      • (ii) TITLE OF INVENTION: Propanoic Acid Derivatives that Inhibit the Binding of Integrins to their Receptors
      • (iii) NUMBER OF SEQUENCES: 1
      • (iv) CORRESPONDENCE ADDRESS:
        • (A) ADDRESSEE: Rockey, Milnamow & Katz, Ltd.
        • (B) STREET: 180 N. Stetson Avenue, 2 Prudential Plaza, Suite 4700
        • (C) CITY: Chicago
        • (D) STATE: IL
        • (E) COUNTRY: U.S.A.
        • (F) ZIP: 60601 1
      • (v) COMPUTER READABLE FOR:
        • (A) MEDIUM TYPE: Floppy disk
        • (B) COMPUTER: IBM PC compatible
        • (C) OPERATING SYSTEM: PC-DOS/MS-DOS
        • (D) SOFTWARE: Patent In Release #1.0, Version #1.30
      • (vi) CURRENT APPLICATION DATA:
        • (A) APPLICATION NUMBER:
        • (B) FILING DATE:
        • (C) CLASSIFICATION:
      • (viii) ATTORNEY/AGENT INFORMATION:
        • (A) NAME: Katz, Martin L.
        • (B) REGISTRATION NUMBER: 25,011 1
        • (C) REFERENCE/DOCKET NUMBER: TEX4542P0412US
      • (ix) TELECOMMUNICATION INFORMATION::
        • (A) TELEPHONE: 312-616-5400
        • (B) TELEFAX: 312-616-5460
    2. (2) INFORMATION FOR SEQ ID NO:1:
      • (i) SEQUENCE CHARACTERISTICS:
        • (A) LENGTH: 26 amino acids
        • (B) TYPE: amino acid
        • (C) STRANDEDNESS: single
        • (D) TOPOLOGY: linear
      • (ii) MOLECULE TYPE: protein
      • (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 1:
        Figure imgb0032
    SEQUENCE LISTING
    1. (1) GENERAL INFORMATION:
      • (i) APPLICANT: Biediger, Ronald J.; Holland, George W.; Kassir, Jamal M.; Market, Robert V.; Li, Wen; Scott, Ian L. and Wu, Chengde
      • (ii) TITLE OF INVENTION: Propanoic Acid Derivatives that Inhibit the Binding of Integrins to their Receptors
      • (iii) NUMBER OF SEQUENCES: 1
      • (iv) CORRESPONDENCE ADDRESS:
        • (A) ADDRESSEE: Rockey, Milnamow & Katz, Ltd.
        • (B) STREET: 180 N. Stetson Avenue, 2 Prudential Plaza, Suite 4700
        • (C) CITY: Chicago
        • (D) STATE: IL
        • (E) COUNTRY: U.S.A.
        • (F) ZIP: 60601
      • (v) COMPUTER READABLE FORM:
        • (A) MEDIUM TYPE: Floppy disk
        • (B) COMPUTER: IBM PC compatible
        • (C) OPERATING SYSTEM: PC-DOS/MS-DOS
        • (D) SOFTWARE: Patentln Release #1.0, Version #1.30
      • (vi) CURRENT APPLICATION DATA:
        • (A) APPLICATION NUMBER:
        • (B) FILING DATE:
        • (C) CLASSIFICATION:
      • (viii) ATTORNEY/AGENT INFORMATION:
        • (A) NAME: Katz, Martin L.
        • (B) REGISTRATION NUMBER: 25,011
        • (C) REFERENCE/DOCKET NUMBER: TEX4542P0410US
      • (ix) TELECOMMUNICATION INFORMATION:
        1. (A) TELEPHONE: 312-616-5400
        2. (B) TELEFAX: 312-616-5460
    2. (2) INFORMATION FOR SEQ ID NO: 1:
      • (i) SEQUENCE CHARACTERISTICS:
        • (A) LENGTH: 26 amino acids
        • (B) TYPE: amino acid
        • (C) STRANDEDNESS: single
        • (D) TOPOLOGY: linear
      • (ii) MOLECULE TYPE: protein
      • (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 1:
        Figure imgb0033

Claims (4)

  1. A compound selected from the group consisting of
    (3S)-3-{[(2S)-2-(3-benzyl-5-methyl-2-oxopyridin-1(2H)-yl)hexanoyl]amino}-3-(3',4'-dimethoxy-1,1'-biphenyl-4-yl)propanoic acid,
    (3S)-3-({(2S)-2-[3-(2-chlorobenzyl)-5-methyl-2-oxopyridin-1(2H)-yl]hexanoyl}amino)-3-(3',4'-dimethoxy-1,1'-biphenyl-4-yl)propanoic acid,
    (3S)-3-(1,1'-biphenyl-4-yl)-3-({(2S)-2-[3-(2-chloro-6-methylbenzyl)-5-methyl-2-oxopyridin-1(2H)-yl]hexanoyl}amino)propanoic acid,
    (3S)-3-{[(2S)-2-(3-benzyl-5-methyl-2-oxopyridin-1(2H)-yl)hexanoyl]amino}-3-(1,1'-biphenyl-4-yl)propanoic acid,
    (3S)-3-(1,1'-biphenyl-4-yl)-3-({(2S)-2-[3-(2-chlorobenzyl)-5-methyl-2-oxopyridin-1(2H)-yl]hexanoyl}amino)propanoic acid,
    (3S)-3-{[(2S)-2-(3-benzyl-5-methyl-2-oxopyridin-1(2H)-yl)hexanoyl]amino}-3-(4'-methyl-1,1'-biphenyl-4-yl)propanoic acid,
    (3S)-3-({(2S)-2-[3-(2-chlorobenzyl)-5-methyl-2-oxopyridin-1(2H)-yl]hexanoyl}amino)-3-(4'-methyl-1,1'-biphenyl-4-yl)propanoic acid,
    (3S)-3-({(2S)-2-[3-(2-chloro-6-methylbenzyl)-5-methyl-2-oxopyridin-1(2H)-yl]hexanoyl}amino)-3-(4'-methyl-1,1'-biphenyl-4-yl)propanoic acid,
    (3S)-3-{[(2S)-2-(3-benzyl-5-methyl-2-oxopyridin-(2H)-yl)hexanoyl]amino}-3-(2',6'-dimethoxy-1,1'-biphenyl-4-yl)propanoic acid,
    (3S)-3-({(2S)-2-[3-(2-chlorobenzyl)-5-methyl-2-oxopyridin-1(2H)-yl]hexanoyl}amino)-3-(2',6'-dimethoxy-1,1'-biphenyl-4-yl)propanoic acid,
    (3S)-3-({(2S)-2-[3-(2-chloro-6-methylbenzyl)-5-methyl-2-oxopyridin-1(2H)-yl]hexanoyl}amino)-3-(2',6'-dimethoxy-1,1'-biphenyl-4-yl)propanoic acid,
    (3S)-3-{[(2S)-2-(3-benzyl-5-methyl-2-oxopyridin-1(2H)-yl)hexanoyl]amino}-3-(1,1'-biphenyl-3-yl)propanoic acid,
    (3S)-3-(1,1'-biphenyl-3-yl)-3-({(2S)-2-[3-(2-chlorobenzyl)-5-methyl-2-oxopyridin-1(2H)-yl]hexanoyl}amino)propanoic acid,
    (3S)-3-(1,1'-biphenyl-3-yl)-3-({(2S)-2-[3-(2-chloro-6-methylbenzyl)-5-methyl-2-oxopyridin-1(2H)-yl]hexanoyl}amino)propanoic acid,
    (3S)-3-{[(2S)-2-(3-benzyl-5-methyl-2-oxopyridin-1(2H)-yl)hexanoyl]amino}-3-(2'-methoxy-1,1'-biphenyl-3-yl)propanoic acid,
    (3S)-3-({(2S)-2-[3-(2-chlorobenzyl)-5-methyl-2-oxopyridin-1(2H)-yl]hexanoyl}amino)-3-(2'-methoxy-1,1'-biphenyl-3-yl)propanoic acid,
    (3S)-3-({(2S)-2-[3-(2-chloro-6-methylbenzyl)-5-methyl-2-oxopyridin-1(2H)-yl]hexanoyl}amino)-3-(2'-methoxy-1,1-biphenyl-3-yl)propanoic acid,
    (3S)-3-({(2S)-2-[3-(2-fluoro-6-methoxybenzyl)-5-methyl-2-oxopyridin-1(2H)-yl]hexanoyl}amino)-3-(4-methylphenyl)propanoic acid,
    (3S)-3-({(2S)-2-[3-(2,6-dimethylbenzyl)-5-methyl-2-oxopyridin-1(2H)-yl]hexanoyl}amino)-3-(4-methylphenyl)propanoic acid,
    (3S)-3-({(2S)-2-[3-(3,5-dimethylbenzyl)-5-methyl-2-oxopyridin-1(2H)-yl]hexanoyl}amino)-3-(4-methylphenyl)propanoic acid,
    (3S)-3-({(2S)-2-[3-(2,6-dichlorobenzyl)-5-methyl-2-oxopyridin-1(2H)-yl]hexanoyl}amino)-3-(4-methylphenyl)propanoic acid,
    (3S)-3-({(2S)-2-[3-(2-chloro-6-fluorobenzyl)-5-methyl-2-oxopyridin-1(2H)-yl]hexanoyl}amino)-3-(4-methylphenyl)propanoic acid,
    (35)-3-({(2S)-2-[3-(2,6-difluorobenzyl)-5-methyl-2-oxopyridin-1(2H)-yl]hexanoyl}amino)-3-(4-methylphenyl)propanoic acid,
    (3S)-3-(1,3-benzodioxol-5-yl)-3-({(2S)-2-[3-(2,6-difluorobenzyl)-5-methyl-2-oxopyridin-1(2H)-yl]hexanoyl}amino)propanoic acid,
    (3S)-3-(1,3-benzodioxol-5-yl)-3-({(2S)-2-[3-(2-chloro-6-fluorobenzyl)-5-methyl-2-oxopyridin-1(2H)-yl]hexanoyl}amino)propanoic acid,
    (3S)-3-(1,3-benzodioxol-5-yl)-3-({(2S)-2-[3-(2,6-dichlorobenzyl)-5-methyl-2-oxopyridin-1(2H)-yl]hexanoyl}amino)propanoic acid,
    (3S)-3-(1,3-benzodioxol-5-yl)-3-({(2S)-2-[3-(2,6-dimethylbenzyl)-5-methyl-2-oxopyridin-1(2H)-yl]hexanoyl}amino)propanoic acid,
    (3S)-3-(1,3-benzodioxol-5-yl)-3-({(2S)-2-[3-(3,5-dimethylbenzyl)-5-methyl-2-oxopyridin-1(2H)-yl]hexanoyl}amino)propanoic acid,
    (3S)-3-(1,3-benzodioxol-5-yl)-3-({(2S)-2-[3-(2-fluoro-6-methoxybenzyl)-5-methyl-2-oxopyridin-1(2H)-yl]hexanoyl}amino)propanoic acid,
    (3S)-3-({(2S)-2-[3-(2-chlorobenzyl)-5-methyl-2-oxopyridin-1(2H)-yl]hexanoyl}amino)-3-(3,4-diethoxyphenyl)propanoic acid,
    (3S)-3-(3,4-diethoxyphenyl)-3-({(2S)-2-[3-(2,6-difluorobenzyl)-5-methyl-2-oxopyridin-1(2H)-yl]hexanoyl}amino)propanoic acid,
    (3S)-3-({(2S)-2-[3-(2,6-difluorobenzyl)-5-methyl-2-oxopyridin-1(2H)-yl]hexanoyl}amino)-3-(3-ethoxyphenyl)propanoic acid,
    (3S)-3-({(2S)-2-[3-(2-chloro-6-fluorobenzyl)-5-methyl-2-oxopyridin-1(2H)-yl]hexanoyl}amino)-3-(3-ethoxyphenyl)propanoic acid,
    (3S)-3-({(2S)-2-[3-(2-chlorobenzyl)-5-methyl-2-oxopyridin-1(2H)-yl]-3-methylbutanoyl}amino)-3-(4-methylphenyl)propanoic acid,
    (3S)-3-({(2S)-2-[3-(2-chlorobenzyl)-5-methyl-2-oxopyridin-1(2H)-yl]-4-methylpentanoyl}amino)-3-(4-methylphenyl)propanoic acid,
    (3S)-3-(1,3-benzodioxol-5-yl)-3-({(2S)-2-[3-(2-chlorobenzyl)-5-methyl-2-oxopyridin-1(2H)-yl]-4-methylpentanoyl}amino)propanoic acid,
    (3S)-3-(1,3-benzodioxol-5-yl)-3-({(2S)-2-[3-(2-chlorobenzyl)-5-methyl-2-oxopyridin-(2H)-yl]-3-methylbutanoyl}amino)propanoic acid,
    (3S)-3-(1,3-benzodioxol-5-yl)-3-({(2S)-2-[3-(2-chlorobenzyl)-5-methyl-2-oxopyridin-1(2H)-yl]-3-phenylpropanoyl}amino)propanoic acid,
    (3S)-3-({(2S)-2-[3-(2-chlorobenzyl)-5-methyl-2-oxopyridin-1(2H)-yl]-3-phenylpropanoyl}amino)-3-(4-methylphenyl)propanoic acid,
    (3S)-3-(1,3-benzodioxol-5-yl)-3-(((2R)-2-(1-benzyl-5-methyl-2-oxo-1,2-dihydropyridin-3-yl)hexanoyl)amino) propanoic acid,
    (3S)-3-(1,3-benzodioxol-5-yl)-3-(((2S)-2-(3-benzyl-5-methyl-2-oxo-1 (2H)pyridinyl)hexanoyl)amino) propanoic acid or a pharmaceutically acceptable salt thereof.
  2. A pharmaceutical composition comprising:
    a compound of claim 1 in a pharmaceutically acceptable carrier.
  3. Use of a compound according to claim 1 for manufacturing a medicament for treating a disease selected from the group consisting of asthma, atherosclerosis, rheumatoid arthritis, allergy, multiple sclerosis, lupus, inflammatory bowel disease, graft rejection, contact hypersensitivity, type I diabetes, leukemia, and brain cancer.
  4. A compound according to claim 1 for use as medicament.
EP01125495A 2000-11-06 2001-11-06 Propanoic acid derivatives that inhibit the binding of integrins to their receptors Expired - Lifetime EP1213288B1 (en)

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